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Integrative Physiology of Fasting

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 Integrative Physiology of Fasting
Stephen M. Secor*1 and Hannah V. Carey2

ABSTRACT
Extended bouts of fasting are ingrained in the ecology of many organisms, characterizing aspects
of reproduction, development, hibernation, estivation, migration, and infrequent feeding habits.
The challenge of long fasting episodes is the need to maintain physiological homeostasis while
relying solely on endogenous resources. To meet that challenge, animals utilize an integrated
repertoire of behavioral, physiological, and biochemical responses that reduce metabolic rates,
maintain tissue structure and function, and thus enhance survival. We have synthesized in this
review the integrative physiological, morphological, and biochemical responses, and their stages,
that characterize natural fasting bouts. Underlying the capacity to survive extended fasts are
behaviors and mechanisms that reduce metabolic expenditure and shift the dependency to lipid
utilization. Hormonal regulation and immune capacity are altered by fasting; hormones that trigger
digestion, elevate metabolism, and support immune performance become depressed, whereas
hormones that enhance the utilization of endogenous substrates are elevated. The negative energy
budget that accompanies fasting leads to the loss of body mass as fat stores are depleted and
tissues undergo atrophy (i.e., loss of mass). Absolute rates of body mass loss scale allometrically
among vertebrates. Tissues and organs vary in the degree of atrophy and downregulation of
function, depending on the degree to which they are used during the fast. Fasting affects the
population dynamics and activities of the gut microbiota, an interplay that impacts the host’s fasting
biology. Fasting-induced gene expression programs underlie the broad spectrum of integrated
physiological mechanisms responsible for an animal’s ability to survive long episodes of natural
fasting. © 2016 American Physiological Society. Compr Physiol 6:773-825, 2016.

Introduction which homeostasis is compromised due to the loss of tissue

All animals require at some stage of their life, if not all, the
acquisition and ingestion of food. Food provides the fuel and
supportive compounds for all of the body’s activities from the
most routine of cellular processes to movement, growth, and
reproduction. Animal food habits run the gamut from mono-
typic diets to a relatively limited selection of foods, to very
catholic diets that include both plants and animals. Feeding
habits are likewise diverse, arranged over a spectrum of feed-
ing frequencies, from near constant feeding and digestion to
cases in which digestion is a relatively rare event. Furthering
this complexity of food and feeding habits is that both can
vary seasonally as a function of animal activity, ambient tem-
perature, and food and/or water availability. Generally, a bout
of feeding and digestion is followed by an episode of digestive
quiescence (i.e., fasting). If feeding is frequent, such fasting
bouts are relatively brief, during which the animals experi-
ences only a modest fluctuation in energy flux and homeosta-
sis. For extended fasting bouts, the animal endures with time
a compounding negative energy budget. For the majority of
such cases, extended episodes of fasting are predictable and
are ingrained into the species’ or population’s natural and life
history tactics. These species employ an adaptive repertoire
function (83, 305).
While all animals alternate between bouts of feeding and
fasting, it is those species that experience prolonged episodes
of fasting that have garnered the most attention. The focus
of many such studies is on a specific life history event (e.g.,
reproduction and care of young) or natural history (e.g., hiber-
nation, estivation, or migration) that includes an extended
period of not eating. For over a century, scientists have inves-
tigated how animals survive fasts relying only on endogenous
resources. Studies have examined how metabolic depression
and switches in substrate utilization aid survival during fast-
ing, and how tissues and organ systems vary in their responses
to fasting and refeeding. Such inquiry has led to a wealth
of information on the integrative physiology of fasting, but
many gaps remain. Such inquiry is sometimes complicated
by the inability to easily separate responses that are dis-
tinctly attributed to fasting from those that stem uniquely from
the life/natural history event itself. Likewise, responses to
* Correspondence to ssecor@ua.edu
1 Department of Biological Sciences, University of Alabama,
Tuscaloosa, Alabama, USA
2 Department of Comparative Biosciences, School of Veterinary

of behavioral, physiological, morphological, and biochemi- Medicine, University of Wisconsin, Madison, Wisconsin, USA
cal responses that maintain homeostasis and prolong survival Published online, April 2016 (comprehensivephysiology.com)
while existing on endogenous stores of energy (361, 574). DOI: 10.1002/cphy.c150013
Fasting is therefore distinct from starvation, the endpoint at Copyright © American Physiological Society.

Volume 6, April 2016 773

Physiology of Fasting
refeeding may be enhanced or masked by concurrent changes
associated with the shift in the animal’s life or natural history
state.
The balance of energy flux in an animal (intake vs. out-
put) is a constantly sliding point on a continuum bookended
between fully nourished and starvation. If the level of feed-
ing is such that the intake of metabolizable energy is less
than the energy expended, the animal is experiencing a neg-
ative energy budget and losing mass. Behavioral and phys-
iological responses may lead to an increase in food intake
and absorption efficiencies, and/or a decrease in metabolic
expenditure.
The focus of this review is on the structural and functional
responses to bouts of fasting (i.e., absence of feeding) and the
subsequent resumption of feeding in vertebrates. For the most
part, we restrict our coverage to fasts that would occur natu-
rally in free-living animals and avoid the body of literature on
responses to artificially imposed food withdrawal in species
that do not typically fast in the wild, and to responses to
food/caloric restriction. The capacity to withstand and recover
from prolonged periods of food deprivation stems from pos-
sessing sufficient nutrient stores, engaging adaptive responses
(i.e., adjustments in behavior, physiology, and/or energy and
intermediary metabolism) that ensure the optimal use of those
stores, maintaining biochemical homeostasis, and retaining
the ability to obtain and assimilate a meal. When possible
we draw from field studies that document natural history and
fasting behavior, and from laboratory studies that explore
the physiological, morphological, and molecular responses to
fasting and refeeding.
Biology of Fasting
Despite the tremendous diversity of food and feeding habits,
feeding and digestion follow a relatively standard repertoire
of organ, tissue, and cellular activities. Food is manipulated
within the mouth (with or without mastication) and actively
transported (i.e., swallowing and esophageal peristalsis) to
the stomach or intestine (if a stomach is lacking). Within the
stomach, food is partially degraded by hydrochloric acid and
the proteolytic enzyme pepsin before moving into the small
intestine. Within the small intestine, pancreatic (e.g., trypsin,
amylase, and lipase) and intestinal (disaccharidases and pep-
tidases) enzymes cleave triglycerides, poly- and disaccha-
rides, and small proteins into their basic nutritive components
of monosaccharides, amino acids/dipeptides, glycerol, mono-
glycerides, and fatty acids. These products, together with vari-
ous ions, minerals, and vitamins, are transported by passive or
facilitated active mechanisms either transcellularly or paracel-
lularly across the intestinal epithelium directly or indirectly
(e.g., mammalian chylomicrons via the lymphatic system)
into circulation. Depending on the immediate metabolic needs
of the animal, absorbed sugars, amino acids, and fatty acids
can either be catabolized or channeled into storage (e.g., glu-
cose to glycogen and fatty acids and glycerol to triglycerides)
774
Comprehensive Physiology
or synthesis (e.g., amino acids into proteins). If the nutrient
pipeline from the intestine to tissues is continuously flowing,
then the metabolic needs of the animal can be constantly met
by feeding, digestion, and absorption.
However, animals in nature rarely experience continuous
intake of food. Even if food is seemingly unlimited, animals
eat and digest following a very rhythmic circadian pattern.
The smallest endotherms (e.g., hummingbirds and shrews)
maintain a near constant assimilation of energy to fuel their
exceedingly high metabolic rates, but cease feeding during
bouts of torpor (237,330,396). If food becomes limited, feed-
ing is less frequent and may stop. Some phocid seal pups
are nursed almost continuously for days, but within a few
months are abandoned onshore or on the ice without food
when their mothers return to sea (341). Likewise meal con-
sumption will stop when an animal shifts to activities that are
disassociated from feeding. When feeding ceases the gut emp-
ties, nutrient absorption is restricted to only those compounds
secreted by host tissues, and the flow of ingested metabolites
into catabolic, storage, and synthesis pathways is suspended.
Given that metabolic and protein needs of an animal are con-
tinuous, the source of metabolic fuel and amino acids for
protein synthesis transitions with fasting from a mixture of
dietary and endogenous substrates to endogenous resources
alone.
While the reason for a fast (e.g., dormancy, egg/young
attending, reduced feeding opportunities, etc.) will often dic-
tate its duration, it is the amount and quality of available
endogenous resources and the innate physiological mech-
anisms employed to efficiently use those resources that
determine how long an individual can survive fasting. Fast-
ing survival ultimately depends on the amount of sufficient
energy and structural resources to meet metabolic and home-
ostatic challenges and the ability to withstand abiotic stresses,
depressed immune function, and parasite load.
The capacity to withstand and recover from prolonged
episodes of fasting is manifested in suites of fasting responses
that serve to collectively reduce the rate of dependency on
endogenous resources and maintain tissue integrity and func-
tion. Characteristic is the downregulation of tissue function
and structure (i.e., atrophy) that serves to depress cellular
metabolism and hence reduce the rate of substrate catabolism
and tissue degradation. The concurrent switch from carbo-
hydrate to lipid metabolism stems from the near depletion
of glycogen stores and a new reliance on the catabolism of
energy-dense lipid stores.
Inherent to the adaptive schedule of life and natural his-
tory events that include bouts of fasting is the time when
feeding resumes. At this time, fasting responses are curtailed
or reversed, previously dormant tissues are reactivated, the
body resumes its intake of exogenous nutrients, and begins to
restore depleted glycogen, lipids, and proteins. The ability to
recover rapidly from fasting is as important as the capacity
to withstand the fast.
An alternative outcome to fasting is death from starva-
tion. In the wild, animals do starve to death when they have
Volume 6, April 2016
Comprehensive Physiology
nearly depleted glycogen and fat stores and have catabolized
a significant amount of body protein. Losing 40% to 50% or
more of body mass is considered lethal (157, 321). Accounts
of starvation are attributed to uncharacteristic long episodes
of very cold weather, low food availability, or drought
(279, 553, 556, 597). Well documented are instance of water-
fowl and game birds that after experiencing especially low
temperatures and lack of food were found dead, emaciated,
and devoid of fat and flight muscle tissue (69, 225, 553, 586).
Drought conditions in eastern Australia in 1982 reduced popu-
lations of red and gray kangaroos (Macropus rufus, M. gigan-
teus) by 40%, and in the following year a drought in south-
ern Africa reduced herds of buffalo (Syncerus caffer), impala
(Aepyceros melampus), warthog (Phacochoerus africanus),
zebra (Equus quagga), and wildebeest (Connochaetes gnou)
by as much as 90% (85, 572). Abandoned by their parents
because of low foraging success, king penguin (Aptenodytes
patagonica) chicks succumb to starvation after 100 to 150
days of fasting (102, 531).
The terms fasting and starvation have been used, some-
times interchangeably in the same report, for more than a
century to identify the postabsorptive period for an animal
(26,99,260,360,471,514,605). This has generated some con-
fusion given that they represent distinctly different stages of
food deprivation and possess different physiologies (305).
Fasting is an innate component of many organisms’ natural
history that evokes an integrative array of behavioral, morpho-
logical, metabolic, and physiological adaptations that serve
to reduce metabolic expenditure and preserve homeostasis
(45, 230, 386, 567). Fasting is better viewed in an ecological
context, not as a nutritional stress, but often as a tactic for
averting stress in the face of competing demands for time or
other resources (386). Fasting animals, therefore, live within
the limits of homeostatic tolerance and can continue to do so
with a constant supply of oxygen and endogenous substrate,
and the ability to remove or store metabolic end products (e.g.,
CO2 , urea, and/or uric acid). If loss of homeostasis is immi-
nent with further fasting, animals may abandon the fasting-
associated behavior (e.g., egg incubation) and search for food,
hence prioritizing survival over the immediate rewards of the
behavior (e.g., breeding success) (10, 226, 321, 462).
Starvation is a nonadaptive event that involves the patho-
logical loss of homeostasis due to the reduction in vital organ
performance (83,305). With the sequential depletion of glyco-
gen and then fat, tissue proteins are degraded at an accelerated
rate to provide amino acids for metabolic pathways and gluco-
neogenesis. Since proteins are less energy dense and contain
more water than fats, body and tissue loss is more rapid. The
time from the onset of starvation to death is a function of body
size, metabolic rate, and how long organs can tolerate the sal-
vaging of their proteins before they are unable to sustain life-
maintaining performance. Also characteristic of starvation is
an additional increase (beyond that which drives lipolysis and
gluconeogenesis) in the release of glucocorticoids (e.g., cor-
ticosterone and cortisol) which stimulates protein catabolism
(293, 468, 596).
Volume 6, April 2016
Physiology of Fasting
The distinction between fasting and starving, or when a
fasting individual had entered starvation, is not always clear.
Criteria for entering a state of starvation include increases
in activity (e.g., food searching and nest abandonment), a
switch in substrate utilization from lipids to amino acids, rapid
increase in daily body mass loss, and increases in plasma urea
and/or uric acid (99, 463). Starvation has been identified as
the transition point from fasting Phase II (dominated by lipid
utilization) to Phase III (protein utilization) or in the later
stages of Phase III when there is a reduced or no possibility
of recovery with refeeding (see Phases of Fasting).
Why and When Do Animals Fast
Central to this discussion is the question of why and when
do animals fast. For diurnal daily eaters, digestive quies-
cence may span a few hours in the early morning, prior to
the resumption of feeding late in the morning. Similarly for
nocturnal foragers, a fasting state is temporary, positioned
just before nightfall. The circadian pattern of these animals
is characterized by an episode of gut inactivity that follows
the completion of meal digestion and absorption. The focus
of this review is on longer episodes of fasting that are linked
to specific life and natural history events that significantly
reduce or prevent feeding. Conditions for extended fasting
include:
1. Experiencing a seasonal state of dormancy to escape harsh
environmental conditions of low temperatures and food
scarcity (i.e., hibernation) or high temperatures and water
scarcity (i.e., estivation).
2. Engaging in a natural (e.g., migration and molting) or life
history (e.g., reproduction, egg/young care, and develop-
ment) event that separates the animal spatially from its
food source.
3. Experiencing yearly episodes of food shortage while
remaining active.
4. Employing a feeding tactic (e.g., sit-and-wait) that is char-
acterized by extended fasting episodes between infrequent
meals.
The following is a description of naturally occurring fast-
ing states with specific attention to species that exemplify each
of these fasting conditions and whose physiological responses
to fasting has been richly studied (Fig. 1).
Hibernation
Terrestrial, semiterrestrial, and aquatic animals that inhabit
seasonal environments experience extended periods of
reduced food availability and lower ambient temperatures that
can limit locomotion and feeding. In response to the onset
775
Physiology of Fasting Comprehensive Physiology

(A) (B)

Hibernation

(C) (D)

Aestivation

(E) (F)

Migration

(G) (H)

Molting

(J)

(I)

Reproduction

(K) (L)

Development

(M) (N)

Long fasting bouts

Figure 1 (Caption on next page.)

776 Volume 6, April 2016

Comprehensive Physiology Physiology of Fasting

Interbout arousals Spring

Summer
40

Body temperature (°C)

30

20

10

Torpor
0
A S O N D J F M A M J
Time (months)

Figure 2 Circannual body temperature cycle in a 13-lined ground squirrel (Ictidomys tridecemlineatus).
The animal was housed conventionally (Ta ∼ 20◦ C, 12:12 LD with food/water), then moved in September
to a 4◦ C cold room in constant darkness with no food/water. Note spontaneous interbout arousals to
normothermia that interrupt torpor bouts during the hibernation season. Figure courtesy of Sandy Martin,
University of Colorado School of Medicine.

of cooler temperatures, amphibians and reptiles seek refuge
either underwater (under the ice) or in burrows or hibernacula
(224, 435). This safeguards the animals from freezing tem-
peratures and easy predation by winter-active endotherms.
Dictated by lowered temperatures, the metabolic rate and
activity of hibernating amphibians and reptiles are greatly
depressed (192, 361). Hibernating amphibians and reptiles
rely upon body stores of glycogen and fat to fuel their low-
ered metabolic rate, and the absorption of water from their
environment to remain hydrated. Warming temperatures in
the spring accompanied by rainfall cue their emergence from
hibernation and the resumption of feeding. Bouts of ectotherm
hibernation range from 3 to 9 months and increase in duration
with latitude (224, 435).
Mammalian hibernation is likewise characterized by
extended bouts of fasting. Small mammalian hibernators sus-
pend the maintenance of a constant high body temperature,
allowing body temperature to drop to ambient temperature
for 3 to 30 days between short bouts (<24 h) of arousal and
elevated body temperatures (Fig. 2) (342). Energy expendi-
ture during torpor bouts can be reduced to 2% to 10% of basal
metabolic rate (BMR) experienced during normothermic peri-
ods (63,256,515). Small hibernating mammals either continue
to fast during bouts of arousal (e.g., ground squirrels and mar-
mots), or feed during arousal on food that had been previous
cached (e.g., chipmunks and some hamsters) (278). For the
former, hyperphagia in summer and fall promotes accumula-
tion of fat reserves, and fasting lasts from ∼3 to 9 months,
although fasting for as long as 1 year has been reported in a
captive pygmy-possum (Cercartetus nanus) (209). Black and
brown bears also hibernate for 3 to 7 months during winter
(167, 404), but in contrast to small mammalian hibernators,
hibernating bears experience a more modest decline in body
temperature (by 3-5◦ C), and a reduction in metabolic rate up
to 75% of euthermic basal levels (551). Adult female bears
give birth during winter hibernation and nurse cubs while
remaining fasted (167, 404).
Although hibernation is more common for temperate and
arctic mammals, it also occurs in tropical environments. The
Madagascan fat-tailed dwarf lemur (Cheirogaleus medius)
hibernates during the dry season when food and water avail-
ability are low and nighttime temperatures drop below 10◦ C
(127). Some small mammals (e.g., deer mice and ham-
sters) and birds (e.g., hummingbirds) experience short peri-
ods (<24 h) of fasting, inactivity, and depressed body tem-
peratures during daily episodes of torpor (475, 520). Like


Figure 1 Animals that exemplify diverse forms of extended fasting have been valuable for exploring the ecology and physiology of fast-
ing. For hibernation (A and B), illustrated are the 13-lined ground squirrel (Ictidomys tridecemlineatus) and black bear (Ursus americanus);
(72, 74, 248, 262, 404). For aestivation (C and D), illustrated are the African lungfish (Protopterus annectens) and green-striped burrowing
frog (Cyclorana alboguttata) in cocooned state (103, 120, 135, 189, 274, 291, 542); For migration (E and F), illustrated are the green sea
turtle (Chelonia mydas) and the red knot (Calidris canutus) (31, 251). For molting (G and H), illustrated are the king penguin (Aptenodytes
patagonica) and the northern elephant seal (Mirounga angustirostris) (95, 98, 589). For reproduction (I and J), illustrated are the northern
elephant seal and emperor penguin (Aptenodytes forsteri) (141, 142, 320, 463). For development (K and L), illustrated are the juvenile king
penguin (Aptenodytes patagonica) and grey seal (Halichoerus grypus) (97, 102, 148, 412). For natural long bouts of fasting (M and N), illus-
trated are the raccoon dog (Nyctereutes procyonoides) and the Burmese python (Python molurus) (113, 328, 390, 391, 491). Photo Credit: (A)
Lesa Hollen; (B) Lynn Rogers, bear.org; (C) http://en.wikipedia.org/wiki/Protopterus#mediaviewer/File:G%C5%91tehal-2.jpg (D) E.A. Meyer;
(E) Evan D’Alessandro; (F) Theunis Piersma; (G) Katie O’Reilly; (H) Dan Costa; (I) Dan Costa; (J) http://joshsjungle.com/wp-content/uploads/
2011/06/emperor-penguin-and-chick.jpg; (K) http://www.factzoo.com/sites/all/img/birds/king-penguin-chicks.jpg; (L) Andreas Trepte; (M)
http://www.factzoo.com/sites/all/img/mammals/raccoon-dog-nice-coat.jpg; (N) Stephen Secor.

Volume 6, April 2016 777

Physiology of Fasting
hibernation, daily torpor reduces energy expenditure during
daily or nightly periods of low ambient temperatures and
restricted access to food.
Estivation
Estivation refers to states of dormancy that enhance survival
during periodic or seasonal episodes of drought, high tem-
perature, and low food availability (435, 533). The majority
of long-term estivators are aquatic or semiaquatic ectotherms
that respond to the drying of their habitat by burrowing into
the substrate and establishing a state of “nonmobile fossori-
alism” (557). The physiological challenges that face estiva-
tors include fasting, dehydration, the accumulation of urea
and ions, CO2 retention, and metabolic acidosis. Combin-
ing inactivity with mechanisms that depress cell metabolism,
estivators are able to survive long episodes of dormancy by
subsisting on endogenous energy stores (535, 584). The Aus-
tralian frog Cyclorana platycephala and the African lungfish
Protopterus amphibius are projected to survive for as long as
5 and 7 years, respectively, in an uninterrupted estivated state
(332,561). A common strategy used to avoid desiccation once
buried is to surround the body (excluding the nares or mouth)
with a semi-impermeable cocoon formed from layers of dried
epithelium (common among estivating amphibians) or from
a hardened mixture of skin-secreted mucus and soil, char-
acteristic of estivating African lungfishes (223, 324). Estiva-
tion ends with the rehydration of the environment, emergence
from the subterranean chamber, and resumption of activity
and feeding.
Previously studied vertebrate estivators include species
of African lungfishes (Protopterus) and anurans (e.g.,
Ceratophrys, Cyclorana, Neobatrachus, Pyxicephalus, and
Scaphiopus) that routinely spend 10 months of the year in
estivation (435, 453, 496). Salamanders of the genus Amphi-
uma, Pseudobranchus, and Siren likewise remain buried and
dormant for much of the year (207, 306, 432, 435). Dur-
ing dry seasons, species of turtles (Kinosternon flavescens),
lizards (Tubinambis merianae, Varanus albigularis), snakes
(Seminatrix pygaea), and crocodilians (Crocodylus johnstoni)
become inactive either buried under leaf litter or soil, or
sequestered within burrows or crevices and do not feed until
the next rainfall (105, 134, 434, 469, 583).
For birds and mammals, the term estivation is commonly
used synonymously with summer torpor, both generally brief
in duration (∼24 h) (210). The echidna Tachyglossus aculea-
tus, pygmy possums (Cercartetus), bats, assorted rodents,
and several birds including poorwills (Phalaenoptilus nut-
tallii), nightjars (Eurostopodus argus), and Andean hum-
mingbirds (Oreotrochilus estella) have all been documented
to employ short bouts of torpor during the summer (210).
The distinction between estivation and hibernation is fluid,
and some species, such as the edible dormouse, Glis glis,
is capable of hibernation in winter, estivation in summer,
and daily torpor throughout the year when food is limited
(582).
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Comprehensive Physiology
Migration
Seasonal or yearly migrations to feeding, breeding, or over-
wintering grounds characterize the life history of many verte-
brates (145). Because many animals do not feed while in tran-
sit, fasting during migration can be especially challenging for
migrants that travel long distances and expend large amounts
of energy on locomotion (5). Well-cited examples include the
long treks undertaken yearly by passerine birds, shorebirds,
sea turtles, and whales. From breeding to wintering grounds,
distances of 4000 to 5400 km (and maybe as far as 8000 km)
are covered nonstop over 3 to 4 days by the great knot
(Calidris tenuirostris), bar-tailed godwit (Limosa lapponica),
bristle-thighed curlew (Numenius tahitiensis), and the Pacific
golden plover (Pluvialis fulva) (29,31,295,349). Female green
sea turtles (Chelonia mydas) swim 2200 km from foraging
grounds off the coast of Brazil to the Ascension Island to nest
and then subsequently return, possibly without feeding dur-
ing each leg of the trip or during nesting (251). Leatherback
sea turtles (Dermochelys coriacea) likewise swim tremendous
distances (>4000 km) from foraging grounds in the northern
Atlantic Ocean to breeding and nesting sites in the tropics
and subtropics, possibly feeding very little during this south-
ern migration and return (80, 286). Baleen whales, exem-
plified by the humpback whale (Megaptera novaeangliae)
and gray whale (Eschrichtius robustus), migrate from high-
latitude feeding areas to subtropical regions for breeding and
calving (162, 452). It is suspected that whales do not feed
along their migratory routes or during the breeding interim
(107, 452).
Molting
Whereas the molting of skin, fur, or feathers may only mod-
estly impact the feeding habits of most animals, marine birds,
and mammals simultaneously fast while undergoing their
yearly molt. Penguins come ashore and do not feed during
the 2 to 5 weeks necessary to renew their entire plumage
(532, 578). The loss of plumage while molting, hence the
reduction in thermal insulation, prohibits penguins from enter-
ing the subzero Antarctic waters to feed (228). While many
seals fast for brief periods while molting, the southern and
northern elephant seals (Mirounga leonina, M. angustirostris)
spend more than a month on the beach fasting while they molt
(54, 320, 589).
Reproduction/care of young
Extended fasts characterize the reproductive biology of a
select group of marine birds and mammals, as well as
some reptiles, amphibians, and fishes. Species of penguins,
petrels, shearwaters, albatrosses, ducks, and geese experi-
ence fasts of a week to several months while engaged in
courtship, egg incubation, and/or during the care of the young
(10,15,230,296,309,441). For most of these birds, males and
females alternate in incubating spells that range from a few
days to several weeks. The longest bouts of avian fasting are
Volume 6, April 2016
Comprehensive Physiology
experienced by emperor penguins (Aptenodytes forester) that
travel as much as 120 km from the open ocean to breeding
grounds and spend up to 50 days in courtship prior to egg
laying. After the single egg is laid, the female returns to the
sea to feed and the male remains, incubating the egg for the
next nine weeks. Upon her return, she feeds the male and the
recently hatched chick, and the male departs for the sea to feed
and return with food for the chick. The parents then alternate
in 15-day foraging trips for the next 6 months until the chick is
fledged. Hence with each breeding season, the male emperor
penguin will fast for as long as 4 months during severe winter
conditions of −30◦ C and wind velocities of 40 m/s (142).
During the breeding season, adult male otariid (fur seals
and sea lions) and phocid (true seals) seals remain on land or
on the ice fasting and without water for as long as 3 months
during the breeding season (122, 320). Female elephant seals
and other phocid seals fast onshore or on the ice for up to 5
weeks which can include a 1- to 2-week preparturition period
and 4 days to 4 weeks of nursing (53, 122, 141, 320).
Female crocodiles (Crocodilus niloticus and C. porosus)
fast for as long as 3 months as they guard their nest of eggs
(114, 139). For various species of lizards and snakes, females
fast while tending a clutch of eggs (511). Pythons will habit-
ually fast for at least a month prior to egg laying and for at
least two additional months coiled around their eggs until they
hatch (21,581). Females of the possibly extinct gastric brood-
ing frogs (Rheobatrachus silus) were documented to fast for 8
weeks from the time they ingested their eggs until the expul-
sion of fully formed young (555). Mouth-brooding or the
oral incubation of eggs and containment of fry has evolved
independently among fish lineages (418). Among ariid catfish
and cichlids, males and females will hold eggs and/or fry in
their mouths for 7 to 70 days, during which they do not feed
[reviewed in (418)].
Development
Prior to experiencing yearly bouts of fasting attributed to
reproduction or molting, young penguins and pinnipeds may
experience a single or multiple episodes of fasting prior to and
following weaning. For the first 4 months of life, king penguin
(A. patagonica) chicks are fed frequently by their parents and
experience rapid growth to near adult size. The following 5
months are marked by a decrease in parent foraging success,
irregular feedings, and episodes of fasting that range from 1
to 5 months, resulting in a 30% to 68% loss in body mass
(96, 97, 102, 531). During the next 3 months, both parents
regularly feed the chick which then completes growth and
joins them at sea. Otariid seal pups are nursed onshore for 1
to 4 days between 2- and 30-day foraging trips their mothers
make at sea (55, 211, 212, 567). In contrast, phocid seal (true
seals) pups are typically nursed continuously for 4 to 45 days,
after which they are abruptly weaned when the mother departs
to feed at sea and does not return (415). The weaned pup
remains on the ice or land for 2 to 12 weeks, before venturing
into the sea to feed (52, 447, 449).
Volume 6, April 2016
Physiology of Fasting
Seasonal food limitation/intermittent feeding habits
There are many species in addition to those previously noted
that experience prolonged episodes of fasting due to the tem-
poral or spatial patchiness of food and/or as a function of
their foraging and feeding habits. Many fish species expe-
rience a seasonal fast of up to 6 months during the winter
when food is scarce or they are separated from food resources
(128, 457). Cave-dwelling species of fishes and salamanders
(“troglobites”) may experience extended fasts of months to
years due to the cyclic nature of flooding and food availability
(439). Crocodiles (Crocodylus), turtles (Chelodina and Kinos-
ternon), and lizards (Heloderma and Varanus) are known to
cease activity and feeding during the dry summer months
(105, 304, 431, 466, 502). Birds of prey (Buteo and Falco) tol-
erate periods of prey scarcity and may fast for a week at a
time (283, 303, 508). For large mammalian carnivores (e.g.,
wolves and lions), a lack of hunting success can result in
fasts lasting for more than a week (371, 482). The raccoon
dog (Nyctereutes procyonoides) of East Asia is documented
to experience natural fasts of 8 weeks during shallow winter
dormancy (390). Snakes that employ the sit-and-wait tactic of
foraging (e.g., pythons, boas, and rattlesnakes) feed relatively
infrequently and thereby exist predominately in a fasted state
(222, 497).
Physiology of Fasting
Metabolism
An animal begins each fasting bout with a finite quantity
of available fuel that cannot be replenished until feeding
resumes. Therefore, in principal, the duration an individual
can survive without food is determined by the quality and
quantity of endogenous energy stores (e.g., lipids, glycogen,
and protein) and the rates at which those stores are utilized.
The rate of substrate catabolism is a function of metabolic
expenditure, collectively the product of basal metabolism,
thermoregulation, activity costs, and any allocation to
reproduction and offspring development. A common strategy
employed during extended periods of fasting is to engage
mechanisms that reduce metabolic costs and/or alter substrate
utilization. Depressing metabolic expenditures lessens the
daily depletion of endogenous fuels and thus extends the
capacity to survive fasting bouts and provide sufficient
energy to feed again. However, as noted earlier, there
are many instances of fasting where animals are unable
to significantly reduce their metabolic costs. This occurs
when animals are simultaneously fasting and engaged in
energy consuming activities (e.g., mating, territory defense,
migration, incubation of eggs, and feeding of young) (87).
Hence, there is considerable variation among species in the
extent to which metabolic rate is altered during bouts of
fasting. In the following, we address four mechanisms that
contribute to the reduction of metabolic rates during fasting
episodes.
779
Physiology of Fasting Comprehensive Physiology

(A) (B)
0.45 24
Cyprinus carpio Python molurus

0.30 16

kJ/h
0.15 8

0.00 0
0 5 10 15 20 0 3 6 9 12
Hours postfeeding Days postfeeding

(C) (D)
50 Pygoscelis adeliae 4.5 Rattus noviegicus

40 4.0
kJ/h

30 3.5

20 3.0
0 2 4 6 8 10 0 2 4 6
Hours postfeeding Hours postfeeding

Figure 3 Energy expenditure (kJ/h) as a function of days postfeeding for the (A) common carp
Cyprinus carpio, (B) Burmese python Python molurus, (C) Adelie penguin Pygoscelis adeliae,
and (D) laboratory rat Rattus norvegicus. These postprandial metabolic plots illustrate the vari-
ation in metabolic rate during meal digestion and the significant decline in metabolic rate
that occurs upon the completion of digestion. Figures were drawn from data presented in
(86, 163, 289, 492).

Reduction in activity rate by 25% to 1000% (Fig. 3) (489). Cessation of post-

The combined activities of moving, foraging, territory
defense, and thermoregulation account for 50% to 70% of an
individual’s daily energy expenditure (106, 301, 497). During
dormancy of hibernation or estivation, animals tend to remain
completely or partially inactive. Hibernating rodents and
bears characteristically lie in a curled position which reduces
the surface to volume ratio, and therefore heat loss (Fig. 1)
(342). Estivating African lungfish, anurans, and siren sala-
manders are immobile in a cocoon of dried mucus and mud or
fashioned from layers of dried skin (207,223,337,358). Other
anurans and reptiles that estivate without forming a cocoon
are likewise inactive (1, 105, 304, 506, 583). The sit-and-wait
foraging tactic employed by some snakes, associated with
long fasting bouts, involves much less movement and energy
expenditure compared to the active foraging of other snakes
that feed more frequently (222, 497). By severely reducing or
eliminating activity, daily energy expenditure can be reduced
by at least 50%.
Eliminating specific dynamic action
Fasting is inherently characterized by an initial decrease in
metabolic rate due to the cessation of meal digestion and
assimilation. Feeding-induced gastric acid production, gut
motility, enzyme production and release, ion and nutrient
transport, nutrient assimilation, and the biosynthesis of glyco-
gen, fats, and proteins all contribute to increasing metabolic
prandial metabolic response is considered responsible for the
initial reduction in metabolic rate for fasting Antarctic fur
seal (Arctocephalus gazelle) and subantarctic fur seal (Arcto-
cephalus tropicalis) pups (19, 567). The extent that metabolic
rate declines with the onset of fasting reflects the magnitude
to which it is increased during digestion (Fig. 3). Reductions
in metabolic rate that are attributed to ceasing meal digestion
and assimilation range from 25% to 35% for mammals, 65%
to 75% for fishes and amphibians, and up to 90% for some
reptiles (489).
Lowering body temperature
During daily torpor or hibernation, dormant animals
either passively experience (ectotherms) or actively achieve
(endotherms) lower body temperatures (Tb ) (526). Depending
on ambient temperature, hibernating amphibians and reptiles
can experience Tb s below 10◦ C, and for a few, Tb can fall
to a few degrees below 0◦ C (224, 435). As a product of Q10
effects, each 10◦ C drop in Tb is associated with a 50% to 65%
decrease in metabolic rate (384). For example, at a hibernat-
ing Tb of 5◦ C, the garter snake Thamnophis sirtalis possesses
a metabolic rate that is 20% of its standard metabolic rate at
25◦ C (4).
For birds and mammals that experience hibernation or
daily torpor, entrance into torpor is accompanied by reduc-
tions in cardiac, ventilatory, and metabolic activity and

780 Volume 6, April 2016

Comprehensive Physiology
a subsequent fall in Tb that lags behind these parame-
ters (151, 208, 232, 255, 526). However, after metabolism
is actively suppressed by cardiopulmonary and metabolic
adjustments, the passive fall in Tb likely contributes to further
reductions in metabolic rate until a minimum Tb is reached
(208,255). Metabolic rates can fall to as low as 2% of BMR for
small rodent hibernators (63,475), while hibernating bears can
experience a 75% decrease in BMR (551). Thus, regulation
of Tb during torpor is not suspended, but rather is regulated
at a new set-point below which metabolic heat production is
activated to compensate for heat loss (515).
Metabolic depression
Independent of body temperature, the metabolic rate of a
dormant/fasting animal can be further depressed by 30% to
85% via the downregulation of cellular processes, including
the depression of ion pumps, decrease in ion leakage, reduc-
tion in mitochondrial proton leak, and suppression of RNA
and protein synthesis (117, 232). For a detailed discussion
of metabolic depression, readers are directed to a compre-
hensive review of metabolic flexibility in endotherms and
ectotherms in this journal (526). Here, we focus on metabolic
changes related to fasting and refeeding. Following 60 days of
laboratory-induced estivation, the lungfish Protopterus dolloi
experienced a 50% reduction in liver mitochondrial respira-
tion with a concurrent 42% to 55% decrease in citrate syn-
thase activities of the heart, gills, and kidneys (190). Torpid
ground squirrels experience severe depression of translation
and thus dramatically reduce protein synthesis (up to 99%) in
all tissues as exemplified by liver and brain (188, 563, 604).
Specific activity of cytochrome oxidase was lowered by 57%
and 65%, respectively, for the gastrocnemius and pectoralis
muscles of the king penguin chick after 108 days of fast-
ing (148). Following 12 to 14 weeks of laboratory-induced
estivation, protein synthesis in liver of the desert frog Neo-
batrachus centralis was reduced by 67%, contributing in part
to the 55% decrease in liver metabolism and 77% decrease
in whole-animal metabolism (192). In these studies, the sup-
pression of cellular activities is not universal among tissues
during fasting. In two of the studies mentioned above, skele-
tal muscle of N. centralis did not concurrently experience
a depression in protein synthesis and metabolism, and liv-
ers of king penguin chicks did not alter specific activity of
cytochrome oxidase following a 108-day fast (147, 192).
Phases of fasting
Fasting animals utilize endogenous glucose, lipids (e.g., glyc-
erol, fatty acids, and ketone bodies), and amino acids to pro-
duce the ATP necessary to fuel cellular processes. The com-
bination at which these substrates are produced and utilized is
dynamic throughout a fasting bout, and varies among species
as a function of the fasting natural history event, inherent
adaptations to fasting, body size, body condition, body tem-
perature, and metabolic rate. The circulating levels of any
Volume 6, April 2016
Physiology of Fasting
metabolic substrate at any given time represent the outcome
of two dynamic processes. Substrate production or release
adds to the circulating pool, and substrate usage draws from
that pool. Homeostatic mechanisms regulate both the addition
and subtraction steps, thereby establishing a rate of turnover
that matches metabolic need. Rates of substrate turnover for
fasting animals can range from being low, (e.g., ectotherms
during hibernation) to being much higher (e.g., endotherms
during migration or lactation). Quantifying circulating con-
centrations of a substrate can be informative when assess-
ing whether levels are being maintained or altered. However,
inferences on rates of production and usage need to be made
with caution if rates of turnover are not likewise quantified
(538).
Extended bouts of fasting are characterized by distinct
shifts in the source and profiles of substrate utilization (362).
These shifts delineate three phases of fasting, each identi-
fied by a particular pattern of body mass loss and the sub-
strates being metabolized (26, 102, 236, 240, 322, 481). Com-
paratively, the duration of phases are shorter and their tran-
sitions more easily identifiable for birds and mammals than
for ectothermic vertebrates. Ectotherms, due to their lower
metabolic rate and greater capacity for metabolic depression,
are able to fast for much longer durations (>1 year) and the
transitions between phases tend to take more time and are
less definitive (261, 359). The characteristics of each of these
phases are described later and illustrated in Figure 4.
Phase I
Phase I of fasting is relatively short (from a few hours to a
week) and encompasses the transition from meal digestion
Glucose
β-Hydroxybutyrate
Relative levels
Protein use/urea
Mass specific weight loss
Metabolic rate
Glycogen
I II III
Phases
Figure 4 Characteristic profiles of metabolic variables during the
three phases of fasting, including plasma concentrations of glucose,
β-hydroxybutyrate, urea, protein utilization, mass-specific body mass
loss, metabolic rate, and tissue concentrations of glycogen. Placement
of individual profiles with respect to the Y-axis is only illustrative and
not quantitative. Figure adapted, with permission, from Figure 1 in (8).
781
Physiology of Fasting
and assimilation to digestive quiescence and the employment
of fasting responses. The daily rate of body mass loss is rel-
atively high due in part to the emptying of the gut (Fig. 4)
(102,236,567). Hence, this phase is accompanied by an initial
decline in metabolic rate as the energy-consuming processes
of meal digestion and assimilation are suspended (19, 567).
The source of metabolized substrate switches from the pre-
vious meal to complete reliance upon body stores of glyco-
gen, lipids, and protein. During phase I, endotherms may
nearly deplete glycogen stores to maintain glucose availabil-
ity (186, 187, 394, 436).
Phase II
This phase, variable in duration and generally the longest,
encompasses the adaptive steps of substrate utilization and
metabolic provisioning to maintain homeostasis in the face of
fasting (Fig. 4). To optimize metabolic economy, metabolic
rates may be further depressed and lipids now account
for as much as 90% to 98% of the metabolized substrate
(95,430,460,463,567). To preserve tissue structure and func-
tion, amino acid usage is minimized (supporting only 2%-8%
of metabolic needs); however, amino acids are utilized for
continued de novo production of glucose [i.e., gluconeogene-
sis (19,430,567)]. Characteristic of this phase is an increase in
production of lipid-derived ketone bodies that serve as a glu-
cose substitute for tissues (e.g., neural and cardiac) that have
a high preference for glucose (167, 437). Respiratory quo-
tients (RQs) decrease to 0.67-0.75 during this phase, reflect-
ing the oxidation of lipids and ketone bodies (271, 411, 442).
Body mass loss continues through this phase, at a more mod-
est rate as high energy-dense fat stores are slowly depleted
(102,236,567). For many fasting episodes, Phase II ends with
the resumption of feeding.
Phase III
If feeding is not resumed prior to reaching a threshold level
of lipid storage, fasting physiology transitions to Phase III.
This critical period of fasting is characterized by a switch
from lipid to amino acid catabolism (Fig. 4) (412, 463). The
contribution of amino acids to fuel metabolism increases from
4% to 56% for the emperor penguin after it enters Phase III
(463). This switch in substrate utilization may result from the
downregulation of fatty acid oxidation rather than from the
depletion of fat stores (38). Phase III is also characterized
by a decrease in ketone body production, and an increase
in amino acid-based gluconeogenesis (45, 94, 236, 420, 463).
Because proteins possess one-eighth the energy per wet mass
than fat, the rate of body mass loss is accelerated during
Phase III (Fig. 4). Individuals that had been sedentary during
Phase II may abandon their activity (e.g., egg incubation)
during Phase III to search for food (10,16,230). If feeding does
not resume, the continued depletion of proteins and tissues
(i.e., cachexia) will eventually lead to organ failure, loss of
homeostasis, and mortality (i.e., death from starvation).
782
Comprehensive Physiology
Substrate utilization during fasting
Glycogen
The glucose polymer glycogen is stored as discrete vesicles
largely within the liver and skeletal muscles. In response to the
fasting decrease in blood glucose, and triggered by circulat-
ing glucagon, cellular glycogen is serially cleaved enzymat-
ically to form glucose-6-phosphate which is rapidly metabo-
lized within source tissues, or is converted within the liver to
glucose and released into circulation. Given that the overall
quantity of stored glycogen is relatively modest (<5% of liver
mass), birds and mammals tend to rapidly deplete their glyco-
gen stores early in a fast (143, 426). Within the first 24 h of
fasting, liver glycogen concentrations are depleted by 85% to
95% for bats and rodents (Fig. 5) (187, 383, 394, 436). Within
48, 48, and 96 h after the start of a fast, liver glycogen is
depleted by 50%, 67%, and 70%, respectively, for the insec-
tivorus bat Molossus molossus, the American marten Martes
americana, and the sable Martes zibellina (186, 393, 408).
For rodent hibernators, glycogen reserves decline during tor-
por bouts and are then replenished via gluconeogenesis during
interbout arousals (198, 199, 505).
Ectotherms likewise deplete tissue glycogen stores while
fasting, but at a much slower rate. Several days to a week of
fasting lowers liver glycogen by 50% to 75% for the fishes
Acipenser naccarii, Oncorhynchus kisutch, Salmo salar,
Salmo trutta, and Tinca tinca, as well as for the lizard Ano-
lis carolinenesis (Fig. 5) (133, 195, 216, 398, 510, 518). Other
ectotherms apparently spare liver glycogen with fasting, and
only after an extended fast do glycogen levels become sig-
nificantly depleted. Fasts of 5, 6, 12, and 20 months sig-
nificantly reduced liver glycogen, respectively, for the eel
Anguilla anguilla (by 43%), the lungfishes P. annectens
and P. aethiopicus (by 40%), and the anurans Xenopus lae-
vis (by 87%) and Rana esculenta (by 95%) (221, 291, 318,
375). In contrast, after 10 days of fasting, the mudskipper
125 Boleophthalmus boddaerti
Relative change (%) from fed
100
75 Acipenser naccarii
50
Clethrionomys rufocanus
25
Artibeus lituratus & A. jamaicensis
0
0 2 4 6 8 10
Days of fasting
Figure 5 Variation in glycogen depletion with fasting is illustrated
with the relative change in liver glycogen as a function of days postfeed-
ing for the mudskipper Boleophthalmus boddaerti, sturgeon Acipenser
naccarii, bats Artibeus lituratus and A. jamaicensis (combined data),
and vole Clethrionomys rufocanus. Figure drawn, with permission, from
data provided in (195, 329, 383, 436).
Volume 6, April 2016
Comprehensive Physiology Physiology of Fasting

Boleophthalmus boddaeriti experienced a 25% increase in 100 (A)

Arctocephalus tropicalis
liver glycogen (Fig. 5) (274).
In addition to the liver, glycogen is also depleted during 80
fasting from skeletal muscle (by 60%-89% over 1-20 months)
for the lungfishes P. annectens and P. aethiopicus, the teleosts 60
Rutilus rutilus and Perca flavescens, and the anurans X. laevis
and R. esculenta (184, 221, 291, 373-375). Fasting reduces 40
glycogen stores from the brain of Oncorhynchus mykiss (72% 0 9 18 27 36
after 4 days) and S. salar (90% after 7 weeks), and from the 90 (B)
Salmo salar
ovaries of X. laevis (by 98% after 12 months) (375, 516, 518).
Two key enzymes that regulate tissue glycogen content 75
are glycogen synthase and glycogen phosphorylase. The for-
mer, responsible for glycogenesis, is downregulated in the 60

Glucose (mg dL–1)

brain and liver of fasted salmon S. salar (518). The latter,
responsible for glycogenolysis, is upregulated within 14 days 45
0 12 24 36 48
of fasting for the same fish (518). After 2 weeks of refeeding 180 (C)
following a 28-day fast, glycogen synthase is increased and Mirounga angustirostris
glycogen phosphorylase is decreased to values similar to those 155
of fed control fish (518). Similarly, refeeding restored liver
glycogen levels for the fish T. tinca, O. kisutch, and R. rutilus, 130
the lizard A. carolinenesis, and the quail Coturnix coturnix
japonica (133, 143, 216, 317, 373). Refeeding also generated 105
new stores of muscle glycogen for the fish R. rutilus and the 0 12 24 36 48
salamander Proteus anguinus (261, 373). 200 (D) Chen caerulescens atlantica

Glucose
Glucose is metabolized by all tissues; however, it is the pre-
ferred fuel for the central nervous system, renal medulla, and
mature erythrocytes, which necessitates its constant availabil-
ity (448). In the absence of an exogenous source of glucose
during fasting episodes, glucose continues to be available
via the hydrolysis of glycogen, the endogenous production of
glucose (i.e., gluconeogenesis), and mechanisms to reduce the
rate of glucose utilization. Glucose can be synthesized de novo
in the liver and kidneys from amino acids (mainly alanine),
glycerol (resulting from triglyceride lipolysis), ketones, and
recycled lactate and pyruvate (i.e., Cori cycle) (68, 88, 111).
Suppression of glucose use (and hence gluconeogenesis) can
be generated from the downregulation of glycolytic enzymes
and the production of ketone bodies that can substitute for glu-
cose in certain tissues (see Ketone bodies). Fasting declines in
glucose oxidation for the muscles and brains of fishes report-
edly stems from the downregulation of phosphofructokinase,
pyruvate kinase, glyceraldehyde-3-phosphate dehydrogenase,
hexokinase, and aldolase (298, 338, 373, 516). Fasting north-
ern elephant seals can temporarily increase insulin resistance
of adipose tissue to slow the utilization of circulating glucose
(568, 570).
The effects of fasting on plasma glucose concentrations
are variable. In some species, plasma glucose concentration
remains unchanged or decreases at some point after the start
of the fast (Fig. 6). For example, compared to fed/prefast
states, plasma glucose levels remain unaltered following fasts
of 4 to 7 weeks for Atlantic cod (Gadus morhua), breed-
ing and molting king and emperor penguins, black-tailed
150
100
50
0 9 18 27 36
Days of fasting
Figure 6 Plasma concentrations of glucose as a function of days
of fasting for (A) subantarctic fur seal pups (Arctocephalus tropi-
calis) which experiences no significant change in blood glucose, (B)
the Atlantic salmon (Salmo salar) which experiences an initial drop
in blood glucose, (C) northern elephant seal pups (Mirounga angu-
stirostris) which experiences a steady decline in blood glucose with fast-
ing, and (D) greater snow geese (Chen caerulescens atlantica) whose
blood glucose is maintained elevated until the entrance into phase III
before declining. Figure drawn, with permission, from data presented
in (45, 112, 517, 567).
prairie dogs (Cynomys ludovicianus), northern elephant seal
and subantarctic fur seal pups (Fig. 6A), lactating northern
elephant seals, and of 8 months for the subterranean salaman-
der P. anguinus (98, 101, 231, 259, 261, 272, 420, 433, 567). In
general, blood glucose levels likewise remain relatively sta-
ble during hibernation for mammals, with any drop during
torpor reversed during interbout arousals via gluconeogen-
esis (310, 505, 544). In other species, plasma glucose con-
centrations have been observed to: (1) decline early in a fast
and largely remain stable thereafter; (2) decline gradually
throughout the fast; or, (3) remain stable for an extended
period before significantly decreasing (Fig. 6). Plasma glu-
cose decreased within 1, 5, and 7 days of fasting, respec-
tively, for the vampire bat Desmodus rotundus, the martin,

Volume 6, April 2016 783

Physiology of Fasting
and the teleost T. tinca (133, 187, 247). The Atlantic salmon
experiences a 20% decline in plasma glucose within 24 h of
fasting, but no further change for the next 42 days of fasting
(Fig. 6B) (518). Plasma glucose dropped by 30% 3 and 4 days
into a fast, respectively, for the rat and trout O. mykiss, but
did not vary for the next 12 and 10 days of the study (516).
A 70-day fast generated a 55% decrease in plasma glucose
for the rattlesnake Crotalus atrox, after which glucose levels
did not vary until day 182 of the fast when the study ended
(360).
A continuous decline in plasma glucose was observed over
a 28-day fast in Nile tilapia (Oreochromis niloticus) (restored
after 14 days of refeeding), during the 8 to 10 weeks of the
postwean fast for northern elephant seal pups (Fig. 6C), dur-
ing the 4-5 months of underground dormancy for the lizard
T. merianae, during 5 months of fasting (Phases II and III) for
king penquin chicks, and over a 12-month fast for X. laevis
(97,112,134,374). In slight contrast, adult greater snow geese
(Chen caerulescens atlantica) maintained stable plasma glu-
cose levels through Phase II fasting before levels declined
with the transition to Phase III (Fig. 6D) (45). During the first
40 days of fasting adult sea bass (Dicentrarchus labrax) main-
tained blood glucose levels, but for the subsequent100 days
of fasting, glucose concentrations decreased by 27% (601). In
stark contrast and rarely observed during fasting are increases
in blood glucose as recorded for the raptor Buteo buteo, imma-
ture carp (Cyprinus carpio), and lactating northern elephant
seals (43, 88, 201).
Gluconeogenesis occurs chiefly in the liver and secondar-
ily in the kidneys and intestine (68, 395, 423, 538). It has been
suggested that gluconeogenesis can also occur in fish red
muscle; however, more recent evidence lends little support
for this to occur (381, 538). The pathway of gluconeogenesis,
regardless of initial substrate (e.g., pyruvate, lactate, amino
acid, glycerol, or acetoacetate) involves passing through, in
reverse direction, the glycolytic pathway (538). Hence for
gluconeogenesis, enzymes specific to glycolysis (e.g., glucose
phosphate isomerase, hexokinase, aldolase, and glyceraldehy-
des 3-phosphate dehydrogenase) are downregulated, whereas
the enzymes that catalyze gluconeogenic steps (e.g., glucose-
6-phosphatase, pyruvate carboxylase, and phospoenolpyru-
vate carboxykinase [PEPCK]) are upregulated. Seven-week
and 4-month fasts, respectively, for the fishes P. flavescens
and Pleuronectes platessa resulted in significant reduc-
tions in the activities of liver hexokinase and pyruvate
kinase, concurrent with increases in liver PEPCK activity
(184, 381).
The relative contribution of gluconeogenic substrates to
gluconeogenesis is, as might be expected, variable among
fasting animals. For lactating northern elephant seals, it is esti-
mated that glycerol (<3% contribution to gluconeogenesis),
amino acids (14%) and the cycling of lactate through pyru-
vate (Cori cycle) contribute to the gluconeogenic pathway,
(88, 272). Rates of gluconeogenesis increase with fasting for
teleost fishes; however, they are more apt to decline with time
fasting (during Phase II) for mammals (88,116,381,536,601).
784
Comprehensive Physiology
It has been proposed that hibernating arctic ground squirrels
(Urocitellus parryi) restore glycogen during arousal bouts
via a contribution that is approximately 75% from glycerol
and 25% from amino acids (198). Winter fasting in hiber-
nating mammals is accompanied by increases in transcript
and protein levels for genes that regulate gluconeogenesis
(153, 156, 262, 290, 470, 507, 579, 593, 594).
Lipids
Lipids are stored as discrete pads of fat within the body cavity
(e.g., visceral or mesenteric fat), subcutaneously (e.g., blub-
ber), and as intracellular droplets within tissues (e.g., liver
and muscle). Predominately composed as triglycerides, fat
bodies, and droplets originate largely from ingested lipids
when energy intake exceeds energy expenditure, and secon-
darily from fatty acids synthesized from glucose and amino
acid precursors. In preparation for fasting, animals increase
food intake and/or alter their diet to build up body stores of
fat (248, 312, 385). Lipids are efficient metabolic fuels dur-
ing fasting due to their high-energy density (∼39 kJ/g), and
because they are stored largely dehydrated. Lipids possess
approximately eight times the energy content per wet mass
compared to glycogen (glucose) and proteins (amino acids)
(7).
The switch from carbohydrates to lipids as the predom-
inant fuel source is a hallmark of fasting physiology. For
hibernating mammals, this is reflected in seasonal changes
in the expression of genes that regulate the carbohydrate to
lipid switch, including the increased expression of pyruvate
dehydrogenase kinase isoenzyme 4 (PDK4) which inhibits the
conversion of the glycolytic product pyruvate to acetyl-CoA in
the heart, white adipose tissue, and skeletal muscle (64, 477).
Other changes at the mRNA and/or protein levels that facili-
tate the switch from carbohydrate to lipid fuels during hiberna-
tion include increases in carnitine palmitoyltranserferase 1A
(CPT1A), fatty acid binding protein 1 (FABP1), 3-hydroxy-3-
methylglutaryl-CoA synthase (HMGCS2), fibroblast growth
factor 21 (FGF21), and reductions in acetyl-CoA carboxy-
lase 2 (ACACB), stearoyl-CoA desaturase (SCD), and elon-
gation of very long chain fatty acids protein 6 (ELOVL6)
(156, 168, 262, 351, 470, 503, 507, 579, 580).
During a fast, triglycerides are cleaved by lipoprotein
lipase (LPL), adipose triglyceride lipase, hormone-sensitive
lipase (HSL), and monoglyceride lipase into nonesterified
fatty acids (NEFAs) and glycerol, which can either be metabo-
lized within cells or released into circulation to travel through
the body attached to protein carriers (e.g., albumin) (569).
Liver activity and mRNA expression of LPL and HSL increase
by 2- to 3-fold within 2 to 3 weeks of fasting for the Nile
tilapia (O. niloticus) (549). Beta-oxidation of NEFA gener-
ates acetyl-CoA that is shuttled into the TCA cycle, or to a
lesser extent, is used to produce ketone bodies (see below).
Hence, extended bouts of fasting are generally characterized
by a steady decline in body fat stores and elevations in plasma
concentrations of NEFA, glycerol, and ketone bodies.
Volume 6, April 2016
Comprehensive Physiology
(A)
1.5 Arctocephalus tropicalis
1.0
0.5
Fatty acids (mmol L–1)
0.0
0 9 18 27 36
(B)
1.8 Aptenodytes patagonica
1.2
0.6
0.0
0 9 18 27 36
Days of fasting
Figure 7 Plasma concentration of fatty acids as a function of days
of fasting for (A) subantarctic fur seal pups (Arctocephalus tropicalis)
and (B) molting king penguins (Aptenodytes patagonica). Fur seal pups
experience a doubling of fatty acid levels with the onset of Phase II (day
4) and both animals experienced a rise in fatty acids toward the end of
Phase II (day 32). Figures drawn, with permission, from data presented
in (98, 567).
Nonesterified fatty acids
Birds and mammals commonly experience during Phase II
an increase in plasma NEFA on the order of 50% to 100%
(Fig. 7), although a 340% increase was observed for fast-
ing dogs (Fig. 7) (57, 100, 193, 322, 323). Upon the transi-
tion to Phase III, plasma NEFA either immediately decrease
or continue to increase temporarily (97, 98, 100, 226, 272).
For ectotherms, plasma concentrations of NEFA following
a month of fasting did not vary for the turtle Phrynops
hilarii; however, they did increase by 30% for the salaman-
der Euproctus asper and by 65% for the sea bass D. labrax
(124, 261, 601). Following a respective 5 and 8 months of
fasting, plasma NEFA concentrations steadily increased by
50% for the eel A. anguilla and the subterranean salaman-
der P. anguinus (261, 318). In contrast, the toad fish Opsanus
tau and Atlantic cod experienced respectively 72% and 90%
decreases in plasma NEFA after 3 and 5 months of experimen-
tal fasting (42, 543). For small rodent hibernators, NEFAs are
elevated during winter torpor when compared to levels expe-
rienced during the spring, summer, and interbout arousals
during hibernation (28, 34, 310, 401, 443).
In addition to fasting increases in circulating NEFA, the
dynamics of NEFA release and utilization may have selec-
tive components. This is supported by the findings that
the relative concentrations of circulating NEFA may not
match those within adipose tissues, and that during a fast,
the relative concentrations of circulating and tissue NEFA
change (128) (Fig. 8). The selective hydrolysis of triglycerides
via lipases, phosopholipases, and acyltranserfases, combined
Volume 6, April 2016
Physiology of Fasting
(A) Nyctereutes procyonoides
25
0
–25
–50
–75
(B) Crotalus atrox
1000
Relative % difference
800
600
400
200
0
–200
(C) Ursus americanus
200
150
100
50
0
–50
–100
14:0 14:1 15:0 16:0 16:1 17:0 18:0 18:1 18:2 18:3 20:0 20:1 20:2 22:0 22:1 22:5 23:0 24:0 24:1
Fatty acid
Figure 8 Relative differences (in percent compared to fed active ani-
mals) in the concentration of individual fatty acids for (A) the scapular
adipose tissue of the raccoon dog (Nyctereutes procyonoides) following
an 8-week fast, (B) the plasma of diamondback rattlesnakes (Crotalus
atrox) fasted for 180 days, and (C) the plasma of female nonlactating
black bear (Ursus americanus) following several months of hibernation.
Illustrated is the dynamic nature of circulating fatty acids in response
to fasting and the variation of that response among animals. Figure
drawn, with permission, from data presented in (323, 360, 390).
with the preferential transport of selected NEFA into circu-
lation, results in particular classes of NEFA that are utilized
over others during fasting bouts.
For the raccoon dog, an 8-week fast resulted in a dis-
proportionate reduction in short-chain (14-17) saturated fatty
acids (SFA) and monounsaturated fatty acids (MUFAs), and
a concurrent increase in concentrations of long-chain (18-22)
SFA, MUFA, and polyunsaturated fatty acids (PUFAs) of adi-
pose tissues sampled from six sites within the body (Fig. 8A)
(390). Seven months of hibernation reduced the relative con-
centrations of palmitic acid (16:0), palmitoleic acid (16:1),
and α-linolenic acid (18:3), while increasing the concentra-
tions of myristic acid (14:0) and stearic acid (18:0) within the
tail fat of the fat-tailed dwarf lemur (173). A 5-month hiber-
nation season in the echidna T. aculeatus led to reductions
in the relative concentrations of MUFA, specifically palmi-
toleic acid and oleic acid (18:1), and reciprocal increases in
the SFA lauric (12:0), palmitic, and stearic acids, and the
PUFA linoleic acid (18:2) in peritoneal and subcutaneous fat
depots (165). Like the lemur and echidna, a 4-day fast in the
pheasant Phasianus colchicus mongolicus reduced the rela-
tive proportions of palmitic acid, palmitoleic acid, oleic acid,
785
Physiology of Fasting
and α-linolenic acid (389). For the rattlesnake C. atrox, a
182-day fast was accompanied by a decrease in whole body
concentration of SFA (chiefly 16:0) and MUFA (chiefly 18:1)
and an increase in PUFA (e.g., 18:2) (Fig. 8B) (360).
Fasting also affects plasma NEFA concentrations. Hiber-
nation in lactating and nonlactating female black bears (Ursus
americanus) increased plasma concentrations of SFA (namely
16:0), whereas there was no change in MUFA concentra-
tions and a decrease in the concentrations of PUFA (e.g.,
18:3n3; 20:3n3; and 20:5n3) (Fig. 8C) (323). In contrast,
7 months of hibernation in yellow-bellied marmots (Mar-
mota flaviventris) led to a decrease in plasma SFA (e.g.,
16:0), no change in MUFA, and a significant increase in
PUFA (e.g., 18:2) (180). Compared to summer levels for the
European brown bear, Ursus arctos arctos, mid-hibernation
plasma had increased concentrations of palmitic, octadec-
11-enoic (18:1n-7), arachidonic (20:4n-6) acids, and docosa-
hexaenoic (DHA, 22:6n-3) acids relative to fed levels, but
reduced concentrations of heptadecanoic (17:0), stearic, oleic,
γ-linolenic (18:3n-6), α-linolenic acid, and eicosapentaenoic
(EPA, 20:5n-3) acids (266).
These studies demonstrate the variation among species in
the particular classes (SFA, MUFA, and PUFA) and forms of
NEFA that are mobilized from body fat stores during a fast.
SFAs (notably 16:0) are preferentially utilized during fasting
for black and brown bears, raccoon dogs, and rattlesnakes,
though selectively retained in body fat of the echidna and
marmot. Polyunsaturated linolenic and α-linolenic acids are
mobilized during fasting for the fat-tailed dwarf lemur and
marmot, while being retained in fat stores of the raccoon
dog, echidna, rattlesnake, and black and brown bears. The
selective retention (or mobilization) of unsaturated fatty acids
may stem from a species-specific need to maintain (or alter)
membrane integrity and fluidity (397).
While the attention and expectation that fatty acid dynam-
ics during fasting is localized to storage forms of neutral
lipids (i.e., triglycerides), structural polar lipids (i.e., mem-
brane phospholipids) may also exhibit dynamic usage and
retention with fasting. The phospholipids of the brown adi-
pose tissues of rats undergo a decrease in the relative content
of myristic acid (14:0) and palmitoleic acid (16:1), while
increasing the content of linoleic acid (18:2) and arachidonic
acid (20:4) after 10 days of fasting (229). However, 4 days of
fasting had no effect on the fatty acid composition of polar
lipids for the claviculocoracoid adipose tissue, heart, liver, or
the pectoral muscle of the Japanese quail Coturnix coturnix
(35).
Glycerol
Glycerol can serve as a gluconeogenic precursor via its con-
version to glyceraldehyde 3-phosphate and then to glucose
6-phosphatate. The immediate decline and continued main-
tenance of low glycerol plasma concentrations during fast-
ing experienced by subantarctic fur seal pups suggests that
they are channeling glycerol into gluconeogenesis (567).
786
Comprehensive Physiology
A different pattern is observed for fasting king penguin
chicks which experience a doubling of plasma glycerol dur-
ing the latter stages of Phase II and further increases with
the onset of Phase III, before declining (97). Increases in
plasma glycerol have also been documented for the fasting
sea bass D. labrax, the raccoon dog, and prior to Phase III
for molting adult king penguins and lactating northern ele-
phant seals (94,98,272,390,601). However, for these lactating
seals, increases in glycerol levels may reflect the nutritional
dynamics of lactation rather than a response specific to fast-
ing. Plasma glycerol levels were found to oscillate after the
onset of fasting for the salamander P. anguinus, remaining
unchanged for the first 60 days, increasing over the next 60
days, and then decreasing thereafter (until day 240) (261). Fol-
lowing 15 days of refeeding this salamander restored glycerol
levels to its initial prefast concentration (261). Hibernating
13-lined ground squirrels experience an increase in plasma
levels of glycerol 3-phosphate which plays key roles in the
regulation of lipid metabolism and plasma membrane com-
position (154).
Ketone bodies
Characteristic of Phase II fasting is the increased produc-
tion and catabolism of the ketone bodies, acetoacetate and
β-hydroxybutyrate (Fig. 4). Originating from beta oxidation
of NEFA within the liver, both substrates can be converted to
acetoacetyl-CoA which when cleaved to acetyl-CoA enters
the Krebs cycle (464). A benefit of ketone body formation
is that ketones can serve as an alternative metabolic sub-
strate to glucose for the central nervous system, heart, muscle,
and kidneys (175, 423, 464). For example, oxidation rates of
β-hydroxybutyrate within the brain of the teleost O. mykiss
increased by 18-fold within two weeks of fasting (516). A sec-
ond benefit is that an increased reliance on ketones reduces
the amount of amino acids (stemming from protein/tissue
degradation) channeled into gluconeogenesis, thus preserv-
ing protein structure (171, 464). A possible detrimental side
effect of ketone accumulation is a decrease in blood pH
(i.e., ketoacidosis) (68, 83). However, a 15-fold increase in
plasma β-hydroxybutyrate experienced by fasting geese had
no effect on plasma pH (322). Increases in plasma acetoacetate
and β-hydroxybutyrate are considered evidential of increased
ketone production and usage, however, such increases may
only reflect a decrease in utilization (464).
Young and adult birds and mammals experience fasting
increases in plasma acetoacetate and β-hydroxybutyrate, high-
lighted by 15- to 40-fold increases observed for fasting bea-
gles, geese, weaned northern elephant seal pups, hibernating
bears and ground squirrels, and laboratory rats (Figs. 9A-
C) (45, 57, 82, 97, 100, 193, 236, 310, 322, 323, 421, 444, 567).
While ketone levels are maintained through Phase II fasting,
they tend to decline significantly with entrance into Phase III
(Figs. 9B and C) (45, 93, 99, 236).
Ketone metabolism during hibernation is supported
by increased gene expression of the rate-limiting enzyme
Volume 6, April 2016
Comprehensive Physiology Physiology of Fasting

6 (A) Arctocephalus tropicalis for the white-tailed prairie dog (Cynomys leucurus), a find-
ing that is counter to the 62% increase in plasma β-
4 hydroxybutyrate experienced by the black-tailed prairie dog
(C. ludvicianus) in the same study (249). Adult female and
2 male northern elephant seals fasted for 6 and 10 to 12 weeks,
respectively, possessed very low plasma β-hydroxybutyrate
0
levels (0.0-0.17 mmol/L) compared to fasting pups (0.7-
0 9 18 27 36 1.8 mmol/L), suggesting differences in ketone utilization
based on developmental needs (82). Laboratory-induced esti-
12 (B) Chen caerulescens atlantica
vation for 60 days did not alter plasma β-hydroxybutyrate and
β-OHB (mmol L–1)

tissue concentrations of acetoacetate and β-hydroxybutyrate

8
for the lungfish, P. dolloi (190). The livers of these fish (pri-
mary site of ketone synthesis) similarly lacked any change
4
with estivation in the activities of the ketone-synthesizing
enzymes β-hydroxybutyrate dehydrogenase (β-HBDH) and
0 succinyl-CoA ketotransferase (190). Fasts of 60 days and
0 9 18 27 36
up to 150 days, respectively, for the carp C. carpio and sea
2.4 (C) Aptenodytes patagonica bass D. labrax generated no change in plasma concentra-
tions of acetoacetate and no detection of β-hydroxybutyrate
1.6 (501, 601). Plasma levels of β-hydroxybutyrate actually
decreased with fasting for the salmon S. salar (518). Given
0.8 the apparent lack of a ketone response with fasting among
lung and teleost fishes, ketones apparently contribute little to
0.0 fueling their metabolism (or to preserving proteins) during
0 12 24 36 48
episodes of fasting (42, 190, 397, 501, 518, 601).
Days of fasting

Figure 9 Plasma concentrations of β-hydroxybutyrate (β-OHB) as a Triglycerides

function of days of fasting for (A) subantarctic fur seal pups (Arc-
tocephalus tropicalis), (B) greater snow geese (Chen caerulescens
atlantica), and (C) breeding male king penguins (Aptenodytes patag-
onica). For these species, β-OHB steadily increased with fasting how-
ever peaked midway through Phase II fasting for the snow geese and
king penguins before declining and returning to initial levels during
Phase III. Figures were drawn, with permission, from data presented in
(45, 101, 567).
in ketone body synthesis, 3-hydroxy 3-methyl glutaryl-
Coenzyme A synthase 2 (HMGCS2), in the liver, kidney, and
intestine (153, 156, 262, 290, 470, 507, 579). The importance
of this metabolic fuel is underscored by the upregulation of its
transporter, monocarboxylic acid transporter 1 (MCT-1) in the
brain and increased expression of succinyl CoA transferase,
the rate-limiting enzyme for ketolysis, in the heart (477). Like-
wise among terrestrial ectotherms, increases in ketone levels
have been noted during fasting for the anuran Rana sylvatica,
the lizard T. merianae, the rattlesnake C. atrox, and the green
sea turtle (134, 258, 360, 440). Exposed to fasting regimes of
40, 100, and 150 days, the dogfish shark Scylliorhinus canic-
ula experienced on average 5.6- and 86.7-fold increases in
plasma concentrations of acetoacetate and β-hydroxybutyrate,
respectively, compared to time-matched fed controls (601).
Not all instances of fasting induce increases in acetoac-
etate and/or β-hydroxybutyrate. Whereas fasting induced a
20-fold increase in plasma β-hydroxybutyrate in geese, ace-
toacetate level was not affected (322). Five weeks of fasting
led to a 31% decrease in plasma levels of β-hydroxybutyrate
Extended episodes of fasting produce variable responses
in plasma concentrations of triglycerides among different
species and fasting durations. Across 10 days of fasting,
plasma triglyceride levels remained steady for the mink
(Mustela vison) (Fig. 10A), while 6 days of fasting resulted
in a 17% increase in plasma triglycerides for the herring
gull (Larus argentalus) (552). Similarly, plasma triglycerides
increased during the first 6 days of fasting for the yellow
legged gull (Larus cachinnans), then declined over the next
2 days (8). Five weeks into their postweaning fast, north-
ern elephant seal pups experienced a 29% increase in plasma
triglycerides; however, 2 weeks later, levels returned to initial
values (420). An 8-week fast generated a 20% increase in
plasma triglyceride for the raccoon dog (390).
In contrast, 3 and 5 days of fasting lowered plasma triglyc-
eride levels by 50% and 60%, respectively, for the laboratory
rat and Antarctic fur seal pups (19, 58). Tilapia (O. niloticus),
sturgeon (Acipenser naccarii), and trout (O. mykiss) expe-
rience nearly a 70% decrease in plasma triglyceride levels
by 28, 40, and 40 days of fasting, respectively, with lev-
els restored following 3 to 4 weeks of refeeding (Fig. 10B)
(195, 549). Subantarctic fur seal pups experienced an imme-
diate 75% drop in plasma triglycerides through Phase I
that remained low throughout Phase II (567). Six days of
fasting led to near total depletion of plasma triglycerides
for the Burmese python (Python molurus bivittatus) even
though the snake possesses prominent stores of fat (Fig. 10C)
(459).

Volume 6, April 2016 787

Physiology of Fasting Comprehensive Physiology

8 (A) Mustela vison (by 330% after 1 month), and in mammalian hibernators that
do not eat during winter (17, 154, 158, 182, 315, 323, 421, 478,
6 519,541,575). For hibernators, at least, the increase in plasma
mmol L–1

4 Triglyceride cholesterol during fasting appears to stem from the reduction

Cholesterol
in fecal output and bile production, as both are routes for
2 cholesterol removal (421). The heavy reliance on lipids as
0
the primary winter fuel coupled with the increase in plasma
0 2 4 6 8 10 cholesterol points to an efficient use of lipoproteins during
Oncorhynchus mykiss
hibernation. Expression of apolipoprotein A-I, the main pro-
600 (B) tein of high-density lipoproteins (HDL) increases in hiber-
nating ground squirrels in liver and intestine, the two organs
400 that synthesize it (153, 155, 351). Cholesterol levels in both
mg dL–1

HDL and low-density lipopoprotein particles are greater in

200 hibernators compared with active ground squirrels, and HDL
particle size also increases during hibernation (421).
0
0 12 24 36 48 60 72
Protein/amino acids
1600 (C) Python molurus
For fasting animals, the amino acids that are catabolized or
1200 channeled into gluconeogenesis originate largely from the
mg dL–1

800
400
0
0 10 20
Days of fasting
Figure 10 Plasma concentrations of triglycerides and cholesterol as
a function of days of fasting for the (A) trout Oncorhynchus mykiss, (B)
mink Mustela vison, and (C) Burmese python Python molurus. For the
Burmese python, the start of the fast is noted at 3 days postfeeding
when plasma triglycerides peaked. Both the trout and python experi-
enced an initial decrease in plasma triglycerides that was not experi-
enced by the mink. Python possess nondetectable levels of triglycerides
in their plasma once they have completed digestion. Fasting resulted
in a modest decrease in plasma cholesterol for the trout, but remained
unchanged for both the python and mink. Figures were drawn, with per-
mission, from data presented in (41, 195) and (S. Secor, unpublished
data).
Cholesterol
An important role of cholesterol during fasting is reportedly
its part in the transport of triglycerides in lipoprotein parti-
cles (407). However, the fasting-related responses of plasma
cholesterol do not necessarily track those of triglycerides,
and are variable across species (Fig. 10). Fasts of 10, 30, 72,
and 72 days, and of 5 months resulted in 38%, 44%, 62%,
38%, and 23% decreases in plasma cholesterol, respectively,
for the gull L. cachinnans, raccoon dog, sturgeon (A. nac-
carii), trout (O. mykiss) (Fig. 10B), and eel (A. anguilla)
(8, 194, 318). Fasting generated no change in plasma choles-
terol for red-legged partridge (Alectoris rufa), herring gull,
mink (Fig. 10A), Burmese python (Fig. 10C), and northern
elephant seal pups following respective fasts of 4, 6, 10, 30,
and 49 days (41, 420, 465, 491, 552).
In contrast, fasting increases plasma cholesterol in the rap-
tor B. buteo (by 25% and reversed with feeding), the rabbit
degradation of body tissues. Given the combined mass of
an individual’s soft tissues, amino acids theoretically consti-
tute the largest pool of available energy for a fasting animal.
The fasting breakdown of proteins also provides three- and
30 four-carbon citric acid cycle intermediates necessary for fat
catabolism and it also releases water (protein-based tissues
are ∼75% water) which would counter dehydration (245).
Protein catabolism during extended fasts is regulated in part
by shifts in the expression of genes related to protein utiliza-
tion, as documented for hibernating mammals that fast the
entire winter (156, 170, 262, 470, 503, 579, 594). In spite of its
large endogenous energy source, role in fat metabolism, and
glucose and water homeostasis, amino acid metabolism has
several severe drawbacks. First, it requires the breakdown of
proteins that may be essential for tissue structure and function.
While a sufficient amount of labile proteins are available (e.g.,
skin, viscera tissue, blood albumin, and skeletal muscle not
pertinent for locomotion), the continued degradation of enzy-
matic, mechanical, and structural proteins will result in the
deterioration of critical tissues and organs and severe home-
ostatic imbalances that will eventually lead to death. Indeed,
death is imminent once 40% to 50% of the body’s protein
pool is depleted (567). A second drawback is that amino acid
catabolism results in the production of ammonia, which is
toxic, and either has to be immediately released, or detoxified
by being converted to urea or uric acid. The former path is only
available for aquatic vertebrates, and the latter option occurs
at a cost and the need to excrete urea or uric acid, or tolerate
its accumulation. Therefore, many animals that predictably
experience extended fasts possess mechanisms to reduce, for
as long as possible, protein degradation (97, 170, 262, 430).
Fasting associated increases in amino acid catabolism
have been inferred by decreases, as well as increases, in
plasma amino acid concentrations and quantified decreases
in tissue protein (43, 392). For 13-lined ground squirrels, lev-
els of plasma amino acids from summer-fed to winter-fasted

788 Volume 6, April 2016

Comprehensive Physiology
conditions show variable patterns of increase, decrease or
no change (154). For the mink, which has relatively poor
adaptations to fasting, skeletal muscle and liver (but not
plasma) protein levels steadily decline during a single week
of fasting (392). The mink’s concurrent increase in plasma
3-methyhistidine, a constituent of actin and myosin, is evi-
dent of muscle breakdown (392, 598). A 5-day fast decreased
liver protein by 46%, but had no significant effect on mus-
cle protein for the rat (218). Both the trout O. mykiss and
sturgeon A. naccarii experienced significant declines (31%-
56%) in liver and white muscle protein concentrations within
5 days of fasting that coincided for the sturgeon with a 61%
increase in plasma protein concentration (no change for the
trout) (195). Fifteen and 30 days of fasting lead to respec-
tive 14% and 30% decrease in muscle protein for the sea
bass D. labrax and catfish Rhamdia hilarii (233, 343). Imma-
ture carp C. carpio fasted for 50 days had depleted liver and
muscle protein content by a respective 40% and 16%, while
experiencing more than a 300% increase in the concentration
of plasma amino acids (43).
For fasting-adapted animals, plasma amino acid levels
typically remain stable and protein breakdown is modest (i.e.,
employing protein sparing) during Phases I and II (Fig. 11A)
(45, 463, 567). Five and a half months of fasting induced no
change in the protein concentrations of skeletal muscle and
liver for the eel A. anguilla; however, for the last 2-3 months of
that period, plasma protein levels had dropped by 35% (129).
50
(A)
Plasma protein (g L–1)
45
40
35
30
0 9 18 27 36
Days of fasting
160 (B)
Relative change
120
80
40
0 Ammonia/Urea/Uric acid
Figure 11 (A) Plasma concentration of proteins as a function of days
of fasting for the greater snow geese (Chen caerulescens atlantica).
Protein levels remain relatively stable through phase I and II, before
declining with the onset of Phase III (day 30). (B) The relative change
in plasma concentrations of amino acids following 8 weeks of fasting
for the raccoon dog (Nyctereutes procyonoides). While the majority of
amino acids decreased in concentration, two amino acids (glutamine
and serine) increased. Figures drawn, with permission, from data pre-
sented in (45, 390).
Volume 6, April 2016
Physiology of Fasting
It took 6 months of fasting for the frog X. laevis and sala-
mander P. anguinus to begin experiencing declines in muscle
protein (261, 375). Over a 1-month fast, subantarctic fur seal
pups, averaging 16 kg at the start, lost only 4.3 g of protein
per day compared to losing 102 g of fat daily (567). During
their postwean-fast, 30-kg harp seal pups and 100-kg northern
elephant seal pups lose an estimated 8 and 10 g of protein per
day while losing 360 and 600 g of body mass per day, respec-
tively (273, 410). Protein sparing and minimal myofibril loss
is characteristic of the locomotor muscles of estivating frogs
and hibernating bears (348, 550). However, for lactating and
hibernation bears, as well as for lactating seals, the loss of
muscle protein may be unavoidable due to the provisioning
of protein for milk production (123, 372, 550). The entrance
into Phase III fasting is characterized by an elevation in tissue
protein loss as amino acids are increasingly responsible for
fueling metabolism, and are being channeled into gluconeoge-
nesis (45,420,461). For 13-lined ground squirrels, levels of all
but two (lysine and glutamine) of 14 amino acids identified in
a screening of plasma metabolites were lower during hiber-
nation relative to summer (154). That study also identified
an intriguing pattern in which levels of certain N-acetylated
amino acids increase during torpor and are then reduced dur-
ing the subsequent interbout arousal period. This may reflect
a salvage mechanism that spares and recycles essential amino
acids for use in new protein synthesis during winter fasting
(154).
Adding to the dynamics of fasting-generated modulation
of plasma amino acid concentrations are concurrent changes
in the relative contribution of individual amino acids to the
overall pool. The 30% decline in total amino acid concentra-
tion for dogs fasted for three weeks stems from the combined
36% to 71% declines in levels of alanine, glycine, proline,
serine, and threonine, no change in cystine and methionine
levels, and 33% to 81% increases in isoleucine, leucine, and
valine concentrations (57). Eight weeks of fasting resulted in
a 21% decline in plasma amino acid concentration for the rac-
coon dog that was contributed to by 20% to 59% decreases in
plasma levels of alanine, arginine, isoleucine, leucine, proline,
and valine, countered by respective 17% and 51% increases
in glutamine and serine (Fig. 11B) (391). Several fish stud-
ies have observed with fasting the selective release of ala-
nine which is the favored amino acid for gluconeogenesis
(326, 377, 538).
Amino acid oxidation starts with the removal of the α-amino
acid nitrogen as ammonia (NH3 , readily converted to NH4 + ).
Ammonia, due to its toxicity (it impairs membrane poten-
tial, metabolism, and neural function) must be immediately
exported, significantly diluted, or converted to the less toxic
forms of urea or uric acid. The direct excretion of ammo-
nia is only practical for aquatic organisms (fishes and aquatic
amphibians and reptiles). Urea, produced via the ornithine-
urea cycle in the liver, is less toxic, requires less water, costs
789
Physiology of Fasting
approximately 5 mol of ATP per mol of urea synthesized, and
is excreted through gills or by the renal-urinary system (335).
Urea is the principal excretory endproduct of amino acid oxi-
dation of semiterrestreal and terrestrial amphibians and all
mammals. Uric acid, produced likewise in the liver, is syn-
thesized in an anhydrous form (favoring water economy) at a
cost of 7 mol of ATP per mol of uric acid (335). Reptiles and
birds are chiefly uricotelic, however many animals possess
the capacity to produce and excrete ammonia, urea, and uric
acid in varied combinations, depending on their environmen-
tal and feeding/fasting state. Therefore, indices of amino acid
catabolism stem from quantifying urine, plasma, and tissue
levels of ammonia, and the constructed products of urea and
uric acid (93, 227, 461).
For fasting-adapted animals, the suppression of amino
acid oxidation during Phase II is evident by the initial decrease
and retention of modest concentrations of plasma urea and uric
acid until the onset of Phase III (97, 101, 463, 567). With the
transition to increase amino acid usage of Phase III, plasma
urea and uric acid levels rise rapidly. Following 7 weeks of
fasting by breeding king penguins, this transition includes a
13- and 8-fold increase in urea and uric acid plasma con-
centrations, respectively (Fig. 12A) (101). During the first
30 days of a fast, plasma uric acid of greater snow geese
increased steadily by 0.5 mmol L−1 ; however, for the next 5
days (entrance into Phase III), plasma concentrations jumped
by 1.5 mmol L−1 (45). Serum urea nitrogen decrease imme-
diately with the onset of fasting for beagles and remained
lowered over a 3-week fast (57). Plasma concentrations of
6 (A)
Aptenodytes patagonica
4 urea cycle is a common theme in hibernating mammals and
mmol L–1
2 Urea Uric acid
0 hibernating bears suppress protein catabolism, they actually
0 10 20 30 40 50
75 (B)
Buteo buteo
50
mg dL–1
Urea
25
Uric acid
0 lost through ventilation. Some of the liberated ammonia dif-
0 6 12 18 24 30
Days of fasting
Figure 12 Plasma concentrations of urea and uric acid as a function
of days of fasting for (A) breeding male king penguin (Aptenodytes
patagonica) and (B) the common buzzard (Buteo buteo) For the king
penguin plasma urea and uric acid concentrations slowly increased
during phase II fasting and rose more steeply with transition to Phase III
(∼day 35). For the buzzard, both urea and uric acid peak midway
through the fast. Figures were drawn, with permission, from data pre-
sented (101, 201).
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Comprehensive Physiology
ammonia did not change over a full year fast for the anu-
ran X. laevis; however, plasma urea did drop by 50% within
2 months of the fast and returned to prefast levels by the
tenth month of fasting (375). For at least 180 days of fast-
ing, the subterranean salamander, P. anguinus exhibited no
change in plasma urea concentration, however between 180
and 240 days of the fast, plasma urea levels had increased by
31% (261). For this salamander, 4 days of refeeding restored
plasma urea to prefast levels (261).
Animals that experience intermittent short episodes of
fasting exhibit similar profiles of urea and uric acid production
during a more compressed Phase II. For the rat and yellow-
legged gull, the rapid entrance into phase II is met with a
decrease in plasma urea (rat and gull) and uric acid (gull)
(8, 236). Seven to 10 days later, the transition to Phase III
occurs with a 137% increase in plasma urea for the rat and
200% to 300% increases in plasma urea and uric acid for
the gull. For nonfasting adapted animals, the initiation of a
fast is accompanied by an immediate increase in plasma urea
and uric acid. Avian examples include the steady increase
in plasma urea and/or uric acid that peaked at 3, 10, and
13 days at 8, 40, and 5 times prefast levels, respectively for
the red-legged partridge, chicken, and B. buteo (Fig. 12B)
(201, 417, 465). Equally poorly adapted to fasting, the mink
more than doubles plasma urea within 3 days of fasting, and
triples levels 2 days later (392).
Hibernation
Although dormant for 5 to 7 months without eating, drink-
ing, urinating, or defecating, bears lose very little muscle
mass and experience no changes in plasma protein, amino
acids, ammonia, urea, or uric acid during hibernation (339).
Reduced expression during winter of genes that regulate the
is consistent with the preferential use of amino acids dur-
ing winter fasting for gluconeogenesis and the TCA cycle
(156, 170, 470, 579, 580, 594). While this may suggest that
experience elevated levels of protein turnover (27, 339). Pro-
tein catabolism continues during hibernation to produce Kreb
cycle intermediaries, to free up water, and to provide nitro-
gen for milk production. However, the resulting urea does
not accumulate within the body or is excreted, but rather
appears to be hydrolyzed within the gut lumen by microbial
ureases into CO2 and ammonia (27, 403, 456), with the CO2
fuses back into the host and is resynthesized into urea within
the liver, but a significant fraction is used by gut microbes
to synthesize new amino acids and proteins. Absorption of
bacterially derived amino acids (and peptides) across the gut
epithelium could potentially contribute to synthesis of new
amino acids in the liver, although the ability of the hindgut
(where bacterial numbers are greatest in nonruminants) to
absorb amino acids and peptides is much less compared to
the small intestine. The mechanisms by which bears and other
Volume 6, April 2016
Comprehensive Physiology
hibernators benefit from their gut microbes for urea recycling,
and the extent to which this process contributes to nitrogen
conservation during winter fasting are not well understood
and warrant further study (513).
Estivation
African lungfish are ammontelic in water, excreting ammo-
nia by diffusion across the brachial and cutaneous epithelia,
and transition to ureotelism during estivation (291, 292, 335).
To examine amino acid metabolism and nitrogen excretion
of estivating lungfish, studies have employed three experi-
mental treatments; fasting in water, estivating in air (“ter-
restrialization”), and estivating in mud. Over a 46-day fast
in water, P. annectens experienced a doubling and quadru-
pling of daily ammonia and urea excretion rates, respectively
(335). However, during this period, ammonia and urea con-
tent of the muscle, liver, brain, and plasma of this lungfish
did not change (335). In contrast, a 40-day fast in water
did generate significant increases in muscle, liver, brain, and
gut contents of ammonia and urea for the lungfish, P. dolli
(103). Following respective 40 and 46 days of estivation in
air, the lungfishes P. annectens and P. dolli had reduced tissue
ammonia concentrations while experiencing a fairly dramatic
(as much as 10- to 16-fold) increase in tissue urea content
(103, 335). For P. dolli, enzymes of the ornithine-urea cycle,
including glutamine synthetase, carbamoyl phosphate syn-
thetase III, ornithine transcarbamoylase, and argininosucci-
nate synthetase, increased after 40 days of estivation (103).
In this treatment, lungfish oxidize amino acids and the pro-
duced ammonia is rapidly channeled into urea production.
When P. annectens are induced to estivate in mud, their tissue
concentrations of ammonia are likewise depressed (by 80%);
however, tissue urea concentrations remain unchanged. Daily
urea synthesis rates had decreased by 97%, indicating that
ammonia production was significantly depressed during mud
estivation (335). It has been suggested that during natural
subterranean estivation, cocooned lungfish are hypoxic and
metabolically depressed. The lowered metabolic rate thereby
suppresses amino acid oxidation, reducing ammonia produc-
tion and hence urea synthesis (335).
Estivating amphibians can tolerate the accumulation of
tissue and plasma urea to levels exceeding 200 mmol L−1
as documented for Scaphiopus couchii and Cyclorana maini
(Fig. 13) (356, 585). Naturally estivating X. laevis experience
increases of 2- to 3-fold in ammonia concentration and of 15-
to 22-fold in urea concentrations of the liver, thigh muscle, and
plasma (24). Following 6 to 9 months of estivation, plasma and
urine urea levels have increased by 6- and 7-fold, respectively,
for S. couchi (356,357). A 67-day episode of laboratory estiva-
tion generated on average a 40-fold increase in plasma urea for
the Australian anurans Neobatrachus pelobatoides, Neoba-
trachus kunapalari, and Heleroporus albopunctatus (Fig. 13)
(585). Urea levels in a pooled collection of muscles from
estivating Cyclorana and Neobatrachus increased on aver-
age 20-fold (585). Plasma urea concentration had increased
Volume 6, April 2016
Physiology of Fasting
S. lacertina
N. aquilonius
P. adspersus
H. albopunctatus
N. kunapalari
N. pelobatoides
S. couchii
0 100 200 300 400 500 600 700 800 900
mOsm
Figure 13 Plasma urea (stippled) and total osmolality (solid) of active
and fed (red) and aestivated and fasted (blue) greater siren (Siren lac-
ertina), northern burrowing frog (Neobatrachus aquilonius), African bull-
frog (Pxyicephalus adspersus), western spotted frog (Heleioporus albop-
unctatus), Kunapalari frog (Neobatrachus kunapalari), humming frog
(Neobatrachus pelobatoides), and Couch’s spadefoot toad (Scaphiopus
couchii). Duration of aestivation range from 2 to 8.5 months. During aes-
tivation, amphibians accumulate urea in their blood which contributes
in some cases to a doubling of plasma osmolality. Figure drawn, with
permission, from data presented in (160, 337, 356, 585).
by 6.4-fold following respective 80 and 210 to 260 days of
laboratory-induced cocooned estivation for the African bull-
frog Pyxicephalus adspersus and greater siren Siren lacertina
(Fig. 13) (160, 337).
Urea accumulation during estivation does have functional
applications. First, urea can denature proteins and thus dis-
rupt enzyme activity (268). Inhibition of metabolic enzymes
could contribute to the depression of metabolic rate during
dormancy (388). Second, for noncocooning estivators, urea
accumulation and the consequential increase in plasma osmo-
lality (>450 mOsm L−1 ) could shift the osmotic boundary
by lowering the water potential of the animal relative to the
surrounding soil thus facilitating water uptake from the soil
(46, 357, 454). Third, elevated tissue urea would facilitate the
movement of water from the bladders to tissues to maintain
hydration (79). And, fourth, with the return of water to the
environment, the accumulated urea could facilitate rehydra-
tion during the arousal phase of estivation (103). It has been
proposed that increases in protein catabolism during estivation
serves to increase urea synthesis to facilitate water acquisi-
tion and retention in anurans (534). For estivating X. laevis,
plasma amino acid concentration increases 2- to 3-fold and
liver carbamoyl phosphate synthase (first enzymatic step in
the urea cycle) activity increases by 6-fold (24).
Maintaining water balance
For fasts that also include the absence of drinking, animals
possess a broad spectrum of mechanisms to maintain water
balance that is in part a function of their environment, behav-
ior, and ability to conserve water. Compared with aquatic
organisms, maintaining adequate water balance is more com-
plicated for fasting terrestrial vertebrates if rates of water loss
(via evaporation or urine production) exceed rates of water
absorption (if possible) and endogenous water production (via
substrate oxidation and released from tissue breakdown). It is
791
Physiology of Fasting
estimated that the oxidation of 1 g of fat yields ∼1.1 g of water
(almost entirely metabolic) whereas the oxidation of 1 g of
protein results in ∼1.2 g of water (0.45 metabolic, 0.75 pre-
formed) (484). During their 2 month postweaning fast, north-
ern elephant seal pups do not drink; however, they are able
to maintain water balance presumably from the catabolism of
their fat stores (419).
Fasting-related changes in body water content are implied
from changes in hematocrit levels; the decrease, no change,
or increase in hematocrit suggest an increase, no change, or
decrease in body water, respectively. Decreases in hematocrit
were observed over the 1 and 3 months of fasting by greater
snow geese and polar bears (Ursus maritimus), respectively
(20, 45). No changes in hematocrit levels were noted after 7,
12, and 41 days of fasting for the mink, the raptor B. buteo, and
molting king penguins, respectively (93, 201, 474). A fasting
increase in hematocrit, suggestive of water loss, was observed
for king penguin chicks during Phase II and for fasting grey
wolves (97, 136). The predictability of hematocrit levels to
assess hydration state has been questioned, given that hema-
tocrit can vary due to activity, age, period of anesthesia, and
methods of quantification (81).
Unquestionably the greatest challenges to water balance
are experienced by animals that estivate (e.g., lungfishes and
amphibians), due to the loss of body water to the drying envi-
ronment and the concomitant increase in solute concentra-
tions. Laboratory-induced estivation resulted in 27% to 77%
increases in hematocrit for the salamander S. lacertina, and the
anurans N. pelobatoides and P. adspersus (159,337,585). This
magnitude of water loss generates 20% to 200% increases
in plasma Na+ , K+ , and Cl− concentrations, 2- to 63-fold
increase in urea concentrations, and hence as much as a
tripling of osmolality (Fig. 13) (79, 337, 356, 585).
Continued dehydration is eventually lethal. It has been
estimated that for the estivating anurans S. couchii, Scaphio-
pus holbrooki, and Scaphiopus hammondi death is imminent
with the loss of 60% to 65% of body water (47%-48% of
body mass) (356, 548). A lethal limit of losing 38.1% to
44.6% of body mass in water was determined for the anurans
Bufo boreas, Bufo terrestris, Cyclorana platycephala, Hyla
cinerea, Hyla regilla, Notaden nichollsi, and P. adspersus
(337, 347, 548). To prevent death from dehydration, estivat-
ing animals employ several water conserving/water absorb-
ing strategies. Many enter estivation with water stored in
their bladder from which they can later transfer to circulation
(207, 476). African lungfishes, sirens, and anurans surround
the body in a cocoon of dried layers of epidermis and dermis
or one formed from a mixture of mucus and soil (324, 450).
This cocoon impedes the evaporative loss of water to the sur-
rounding soil (324, 337). Anurans that bury without forming
cocoons risk a greater rate of water loss; however, this opens
the door for the eventual movement of water from the soil to
the animal. Water flux between an animal and the immedi-
ate surrounding environment is a function of the differences
in water potential of the animal and soil, with water mov-
ing from higher to lower water potential (46). For estivating
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Comprehensive Physiology
anurans, body water loss continues until the animal achieves a
lower water potential than the soil, facilitated by the increased
osmolality of body fluids (357). Thereafter, water is absorbed
transcutaneously from the soil, usually through a ventral seat
patch (562). In soils (e.g., sand) that characteristically have
low water potential, anurans that do not form cocoons will
pack the soil around them to form an air space between them-
selves and the soil, thus preventing the osmotic transfer of
water from their body to the soil (46).
In contrast, aquatic organisms, or those that have access
to water, may experience a positive water balance. Following
4 months of fasting, the plaice P. platessa experienced 7.6%
to 11% increases in water content of the liver, red muscle, and
white muscle (381). White muscle water content increased by
14% after 2 months of fasting for the winter flounder Pleu-
ronectes americanus (344). Similar levels of increase (4.6%-
15%) in organ (e.g., muscle and liver) and body water content
have been documented after 3 to 18 months of fasting for the
eel A. anguilla, the anurans R. esculenta and X. laevis, and
the salamanders E. asper and P. anguinus (129,221,261,375).
Fasting-induced increases in water concentration stem in part
from the loss of tissue (fat and muscle) and its replacement
by water (344, 369).
Hormonal changes in fasting
A repertoire of endocrine changes would predictably be expe-
rienced during episodes of fasting (26). In the absence of eat-
ing, insulin’s role as a hypoglycemic and lipogenic hormone
would likely diminish, whereas the release of glucagon, given
its role in stimulating glycogenolysis, gluconeogenesis, and
lipolysis, would become enhanced. Similarly, glucocorticoids
would be released to trigger selective utilization of endoge-
nous substrates. Depressed would be hormones that stimulate
gastrointestinal function and feeding. To facilitate the depres-
sion of metabolic rate during fasting, a reduction in levels
of hormones that stimulate metabolism [i.e., triiodothyronine
(T3 ) and/or thyroxin (T4 )] would be expected.
Insulin
Fasting associated declines in plasma insulin have been
observed for a variety of taxa. Fish maintain circulating
insulin levels for 1 to 7 days before they decline sig-
nificantly (by 20%-89%) over the next day to 2 months
(174,234,259,317,397,547). Plasma insulin remains elevated
for 48 h after feeding for the Burmese python before declining
by 97% over the next 8 days (488). For the sable, mink, adult
female northern elephant seal, weaned northern elephant seal
pup, and raccoon dog fasts of 4 days, 5 days, 16 days (early
to late lactation), 5 weeks, and 2 months were associated with
30%, 50%, 63%, 32%, and 50% decreases in plasma levels of
insulin, respectively (Fig. 14) (88, 391, 393, 474, 571). Insulin
concentrations surprisingly do not vary over the 5 weeks of
fasting, either during reproduction or molting, that are expe-
rienced each year by adult king penguins (39, 98, 101).
Volume 6, April 2016
Comprehensive Physiology Physiology of Fasting

Aptenodytes patagonicus Nyctereutes procyonoides

500 30
Glucagon

Glucagon (pg mL–1)

Insulin (µLU mL–1)
400
20

pmol L–1
300 Glucagon

200
10 Insulin
100 Insulin

0 0
90 18

60 12 Cortisol
Corticosterone
nmol L–1

nmol L–1
30 6

0 0
12
60

8
40
nmol L–1

nmol L–1
T4 T4

4 20
T3
T3
0 0
0 10 20 30 40 50 0 15 30 45 60
Days of fasting Days of fasting

Figure 14 Plasma concentrations of glucagon, insulin, corticosterone or cortisol, triiodothyronine

(T3 ), and thyroxin (T4 ) as a function of days fasting for breeding male king penguins (Aptenodytes
patagonicus) and raccoon dogs (Nyctereutes procyonoides). With the exception of glucagon, which
increased with time fasting for both species, plasma concentrations of the other five hormones
experienced contrasting fasting profiles. Figures drawn, with permission, from data presented in
(101, 391).

Glucagon dictated in part by the actions of these steroids in triggering

As expected, fasting increased glucagon levels in immature
carp C. carpio and the trout S. trutta; however, other teleost
fishes lowered their glucagon levels significantly during fast-
ing by as much as 95% (43,174,233,259,380,398). Similarly,
Burmese pythons lowered glucagon levels with fasting by
85% after a 45-day fast (495). King penguins, either molting
or breeding, experienced a steady increase (by 250%) in cir-
culating glucagon during the 5 weeks of Phase II fasting and
the following 2 weeks of Phase III (98, 101). Whereas fasting
generated a doubling in plasma glucagon for the raccoon dog,
it caused no change in glucagon levels for the mink (Fig. 14)
(391, 474).
Glucocorticoids
Fasting could also stimulate the release of the adrenal glu-
cocorticoids cortisol (primarily for fishes and most mam-
mals) and corticosterone (chiefly for amphibians, reptiles,
and birds). The fasting program of substrate metabolism is
gluconeogenesis and protein and lipid catabolism (125, 429).
Modest secretion would support long-term Phase II fast-
ing via the induction of lipolysis, whereas elevated release
is required during phase III to spark increases in protein
metabolism and/or support metabolic expenditure in the
search for food. Migrating sturgeon (Acipenser güldenstädti)
and salmon (Oncorhynchus nerka and O. gorbusha) exhibit
marked increases in plasma cortisol that accompany observed
loss of tissues (282, 355, 397). Five weeks of fasting induced
an 84% increase in plasma cortisol for the fish Garra gotyla
gotyla, while subsequent weeks of fasting (until 9 weeks)
led to the return of fed levels (314). Galápagos marine igua-
nas (Amblyrhynchus cristatus) of low body condition due to
severe reduction of their algae food source during an El Niño
year had higher corticosterone levels (by 50%-200%) com-
pared to individuals with better body conditions collected
during a non-El Niño year (468).
Circulating corticosterone in king penguins did not vary
for the first 4 weeks of the molting fast; however, in the last

Volume 6, April 2016 793

Physiology of Fasting
week of Phase II and into Phase III, plasma levels jumped
by 200% (98). For breeding king penguins, corticosterone
levels remained steady during Phase II and only increased
(150%) following entry into Phase III (101). Mallard ducks
experienced 4- and 6-fold increases in plasma corticosterone
at the end of Phase II and during Phase III, respectively
(48).
During their weaning fast of 4 to 5 weeks, northern ele-
phant seal pups experience a doubling of cortisol levels, and
an increase of 70% to 90% in plasma cortisol was experi-
enced over a 16-day span by lactating northern elephant seals
(88,272,571). A 4-day fast increased plasma cortisol level by
160% for the sable (393). Upon entrance into Phase III, corti-
costerone levels in laboratory rats had risen by 19-fold (100).
Overwintering black bears likewise experience increases in
circulating cortisol; however, winter dormant raccoon dogs
experienced a decline in plasma cortisol suggesting that they
may use an alternative axis to stimulate lipolysis (246, 391).
Thyroid hormones
Facilitating the depression of metabolic rate, and hence low-
ering the rate of energy depletion during fasting episodes,
are steps along the hypothalamus-pituitary-thyroid axis that
reduce the secretion of the thyroid hormones T3 and T4 ,
each a stimulator of metabolism. Among vertebrates, T4 is
the form predominately secreted and is converted, via mon-
odeiodinases, to the more active T3 that has a higher affin-
ity to receptors (36). Fish experience within days of fast-
ing 20% to 65% decreases in plasma concentrations of T3
and T4 (133, 206, 565). Fasting declines in T3 and T4 have
also been documented for king penguins during both the
breeding and molting seasons (98, 101). Hibernating black
and brown bears as well as fasting canids (raccoon dog,
grey wolf, and arctic fox) and mustelids (sable, badger, and
mink) likewise experience significant decreases in T3 and/or
T4 (23, 136, 193, 250, 267, 391, 393, 474). In contrast to these
examples of declines in thyroid hormone levels during fasting,
in other species T3 and/or T4 are maintained, elevated, or fluc-
tuate during the fasting phase, likely reflecting the complexity
of thyroid hormone action on peripheral tissues. Serum levels
of T3 and T4 are elevated throughout the hibernation season
in Richardson’s ground squirrels (Urocitellus richardsonii),
(137,138). However, because of the concomitant reduction in
nuclear T3 receptors and increase in serum binding capacity
of T3 and T4 , thyroid hormone function is likely suppressed
during winter fasting (345, 346). Total serum T3 and T4 are
maintained or increase after 49 days of a postweaning fast in
northern elephant seal pups (420). Furthermore, experimental
fasts of 1 to 7 weeks in the seal pups increase mRNA expres-
sion of deiodinase enzymes (which convert T4 to T3 ) in adi-
pose tissue and muscle, and also increase mRNA expression
of thyroid hormone receptor beta-1, suggesting that cellular
thyroid hormone-mediated activity is upregulated with fasting
duration. This response may be unique for mammals adapted
to prolonged fasting to increase responsiveness of peripheral
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Comprehensive Physiology
tissues to thyroid hormone stimulation, thus facilitating their
lipid-based metabolism (352).
GI peptides
The cessation of feeding, digestion, and assimilation would
signal the suppression (i.e., release and/or production) of hor-
mones, neuropeptides, and paracrine mediators involved in
the regulation of gastrointestinal performance. Without the
need to stimulate, regulate, and/or inhibit gastric, pancreatic,
and intestinal function, circulating GI-regulatory hormones
and neuropeptides would be expected to decline during fast-
ing episodes. Such a response was observed for the Burmese
python which experienced 96%, 83%, and 70% declines in
plasma concentrations of cholecystokinin (CCK), glucose-
dependent insulinotrophic peptide (GIP), and neurotensin,
respectively, after 1 month of fasting (495). In contrast, tissue
levels of these hormones increased in the python’s stomach,
pancreas, and intestines 1 month after their last meal, sugges-
tive of synthesis and storage of these hormones in endocrine
cells until the snake eats again (495). Glucagon-like peptide
(GLP) is a known insulinotropic hormone which for fish also
aids in the regulation of gluconeogenesis (378, 380). Fasts of
28 and 42 days in the teleosts G. morhua and O. mykiss led
to respective decreases in circulating GLP of 90% and 80%
(259, 437).
Adiponectin, leptin, and ghrelin
Released from adipocytes, the hormones adiponectin and lep-
tin are also involved in the regulation of energy expenditure.
The former stimulates fatty acid oxidation, whereas the lat-
ter regulates food intake and other processes that affect fuel
usage and energy balance (382, 400). Circulating concentra-
tions of these hormones are correlated negatively and posi-
tively, respectively, with percentage of body fat (427, 525).
During a fast of 4 to 5 weeks, northern elephant seal pups
experienced a 23% decrease in circulating adiponectin (568).
However, the mink experiences no variation in adiponectin
levels during a 7-day fast (474). Leptin enhances the brain’s
response to satiety signals, thus reducing food intake and con-
sequently, body mass (382). Leptin levels declined with fast-
ing for the mink and Brant’s vole (Lasiopodomys brandtii),
and remained steady thereafter (603). The increase in circu-
lating leptin observed in sciurid rodents in the fall prior to
start of hibernation (109, 181) is consistent with timing of
peak body fat levels and cessation of food intake.
Considered a counterpart to leptin because it stimulates
hunger, circulating ghrelin, produced primarily by the stom-
ach and pancreas, decreased significantly with fasting for
female mink, however it nearly doubled after 7 days of fasting
for male mink (474). In ground squirrels, ghrelin levels are low
during hibernation relative to the active season (252), which
may contribute to the suppression of appetite during winter
fasting. During summer, fasts of 1, 3, or 5 days increased
Volume 6, April 2016
Comprehensive Physiology
circulating ghrelin levels relative to controls, although con-
centrations did not vary with length of the fast (254). Circu-
lating ghrelin may regulate torpor induced by fasting in mice,
because intraperitoneal administration of ghrelin prior to start
of a 24 h fast reduces minimum torpor Tb by about 4◦ C (217).
The effect likely acts through signaling of neurons in the arcu-
ate nucleus of the hypothalamus (217). Fasting also elevates
circulating ghrelin in fish and lead to increased food intake
(558).
Catecholamines
Because catecholamines (dopamine, epinephrine, and nore-
pinephrine) play a role in stress signaling and have been
implicated in the regulation (both stimulatory and inhibitory)
of food intake and substrate metabolism, it is reasonable to
predict their blood and/or tissue levels might vary with the
onset and duration of fasting (132, 406). Outside of clinical
or laboratory rodent studies, fasting responses of cate-
cholamines have been examined only for fishes and hiber-
nating bears. Following 7 days of fasting, hypothalamic con-
tent of dopamine and norepinephrine (but not epinephrine)
increased in trench, whereas goldfish (Carassius auratus)
responded with decreases (20-30%) in dopamine and nore-
pinephrine (132). For European brown bears circulating levels
of epinephrine and norepinephrine decline from the summer
active season to winter hibernation (267).
Nutrient and energy sensing during fasting
AMP-activated protein kinase (AMPK) is a highly conserved
heterotrimeric Ser/Thr kinase that monitors cellular energy
status through increases in the AMP/ATP and ADP/ATP
ratios, along with other signals. Under conditions of falling
energy status, AMPK promotes ATP production by regulat-
ing activity or expression of catabolic proteins and conserves
ATP levels by downregulating biosynthetic pathways (243).
At the whole body level, AMPK regulates energy balance
by activating hypothalamic pathways that induce feeding and
entrains circadian rhythms of metabolism and feeding behav-
ior. Metabolically, AMPK activation during energetic chal-
lenge promotes the transition from glucose to lipid as the main
substrate for cellular oxidation. The regulation of AMPK is
complex, involving neuroendocrine influences and circulating
nutrients.
Most studies on AMPK biology have used laboratory
animals that do not normally undergo extended fasting in
nature. However, given its crucial role in sensing and respond-
ing to changes in fuel status, AMPK is likely involved in
the integrative response to natural bouts of fasting and the
metabolic depression that accompanies some fasting states
(455). Among studies that have examined AMPK in species
that normally fast in the wild are several from hibernating
species (179). In golden-mantled ground squirrels expression
of the active, phosphorylated form of AMPK (pAMPK) in
liver, muscle, and adipose tissue increased after short-term
Volume 6, April 2016
Physiology of Fasting
fasting (up to 5 days) in summer squirrels. In hibernators,
pAMPK was lower in muscle and white and brown adipose tis-
sues during a euthermic arousal compared with the torpid state
(253). However, examination of the expression of AMPK and
pAMPK protein in tissues of 13-lined ground squirrels pro-
duced scant evidence for a major role in metabolic reorganiza-
tion or metabolic depression during hibernation (270). Intrac-
erebroventricular infusion of the AMPK activator, AICAR,
during hibernation in marmots caused resumption of feeding
compared with saline-infused control animals that did not eat
(178). Together these studies suggest that AMPK regulates
food intake and the reorganization of metabolic fuel sources
in fasted hibernators, but more research is needed to clarify
its role (179). In elephant seals late in the postweaning fast,
elevated pAMPK may contribute to the increase in cellular
glucose uptake into WAT cells via upregulation of glucose
transporter 4 (GLUT4) expression (571).
Another signaling pathway that has been proposed to
mediate suppression of carbohydrate catabolism in favor of
lipid oxidation during hibernation is the serine-threonine
kinase Akt (also known as protein kinase B). Because Akt
promotes anabolic and lipogenic pathways, and mediates
the effect of insulin on cellular glucose uptake its activity
would be expected to fall when animals are fasting. Consistent
with this, Akt expression and activity in hibernating bats and
Richardson’s ground squirrels (Urocitellus richardsonii) are
reduced during torpor (brain, kidney, liver, and white adipose
tissue in bats, skeletal muscle, and liver in squirrels) compared
with their nonhibernating counterparts (2, 150), although it
is not clear whether levels remain suppressed during natu-
ral interbout arousals to euthermia when the animals remain
fasted. In marmots, Akt activity in fat and muscle peaks in July
to September during the anabolic phase of the annual cycle
prior to winter fasting (269). In 13-lined ground squirrels
activated (phosphorylated) Akt varies during the hibernation
cycle, with highest levels in liver during the transitions into
and out of torpor (370) whereas in intestine, levels are lowest
in torpor and highest in summer and winter euthermia (177).
Taken together, these results point to tissue specificity in Akt
activity and (presumably) function over the annual hiberna-
tion cycle, consistent with its multiple biological roles in fed
and fasting states.
Fasting and the immune system
During extended episodes of fasting, endogenous resources
are allocated to immediate life sustaining activities while
being diverted from the maintenance of other resource con-
suming systems, including the immune system (48). Fasting
animals are more vulnerable to pathogens when their immune
system is depressed. Such vulnerability can be acerbated by an
increase in energy expenditure (e.g., courtship and egg incu-
bation) and/or exposure to unfavorable environmental condi-
tions (e.g., low temperatures) that will further compromise the
ability to mount an effective immune defense (49, 51, 540).
A compounding factor is the increase in protein catabolism
795
Physiology of Fasting Comprehensive Physiology

with the onset of Phase III, a response that is regulated by
corticosterone/cortisol, which can exert immunosuppressant
effects (480).
The two arms of the immune system include the innate (a
rapid generalized response) and adaptive (a delayed antigen-
specific response) pathways (467). Mallard ducks (Anas
plathyrhnchos) fasted for 12 days (Phase III) experienced
80% and 40% declines in plasma levels of natural antibod-
ies (NAbs, innate immunity) and immunoglobulin Y (IgY,
acquired/adaptive immunity), respectively (Figs. 15A, 15B)
(48). During this fast, the duck’s plasma corticosterone levels
had increased by 7-fold (Fig. 15C). Fifteen days of refeed-
ing restored lost body mass and plasma NAbs and corticos-
terone levels; however, IgY levels remained depressed by 20%
(Figs. 15A-C) (48). A similar response was observed for cap-
tive fasted male king penguins: IgY decreased by 40% and
(A)
1.2 IgY
absorbance units
corticosterone increased by 60% upon the entry into Phase III
fasting (51). During 2 to 3 weeks of egg incubation without
feeding, female eiders (Somateria mollissima) experienced a
25% decrease in an immunoglobulin index (50). Given that
most of the information on the impact of fasting and crit-
ical periods of energy expenditure on immune capacity is
derived from birds, there is a dire need to examine the effects
of selective allocation of energy to different systems (e.g.,
immune) during fasting on health and survivorship in other
animal groups.
Hibernation in species that cease feeding during winter
leads to remodeling of the intestinal immune system in a
manner consistent with preservation of immune capacity but
dampening of proinflammatory processes (313). Compared
with summer-active 13-lined ground squirrels, both torpid and
aroused hibernators have increased numbers of intraepithelial
lymphocytes and lamina propria leukocytes. Numbers of lam-
ina propria B cells are higher during hibernation as is the B
cell product, secretory IgA. IgA contributes to beneficial host-
microbial interactions by binding to bacteria and preventing
their adhesion to epithelial cells. It is also a key regulator of the
composition and activity of the gut microbiota (300). Intesti-

0.8 nal expression of the potent anti-inflammatory cytokine IL-

10, as well as IL-4, increase during hibernation; both of these
cytokines can stimulate IgA synthesis and secretion. Although
0.4
a direct causal connection between winter fasting per se and
these immune changes has not been shown, it is possible that
0.0 some or all are adaptations to minimize deleterious effects
(B) NABs
of the increased gut permeability that accompanies hiberna-
6 tion (71,75). Elevated permeability can increase movement of
bacterial products, such as lipopolysaccharide (LPS), across
agglutination scores

4
the epithelium and induce inflammation in the intestine and
other organs (573). In support, hibernation is associated with
increased epithelial expression of Toll-like receptor TLR5,
2 and reduced expression of TLR4 (144). Binding of TLR4 by
LPS activates the transcription factor NF-κB which can induce
inflammatory responses, whereas TLR5 activation by its lig-
0
and, flagellin, is associated with protective, anti-inflammatory
(C) 90 Corticosterone responses and maintenance of intestinal barrier function. Pro-
longed fasting may also contribute to the general immunosup-
pressive state observed at the whole-body level in hibernating
60
mammals (47).
ng L–1

30
Body and organ mass changes with fasting
As a function of a continuous negative energy flux and deple-
0
fed 48h PII PIII R1 R3 Rt tion of energy stores, extended fasts are characterized by the
Treatment loss of tissue and organ mass, and hence body mass. There is
considerable variation among tissues and organs in the rates of
Figure 15 Plasma concentration of (A) immunoglobulin (IgY), (B) nat- mass loss and how each contributes to overall body mass loss.
ural antibodies (NABs), and (C) corticosterone for fasted and refed Some organs and tissues are catabolized as energy sources
female mallard ducks (Anas platyhyrhychos). Sampling treatments
included fed, 48-h fasted, phase II of fasting (PII), phase III of fasting during fasting (e.g., fat) whereas others lose mass because
(PIII), fasted to PIII and refed for 1 day (RI), fasted to PIII and refed for 3 rates of cell loss exceed rates of proliferation (e.g., small
days (R3), and fasted to PIII and refed to recovery of initial body mass intestine). These tissues lose mass at a faster rate than over-
(Rt). Note the fasting decline in immune function and rapid increase
in corticosterone, both reversed with refeeding. Figures drawn, with all body mass (Fig. 16). In contrast, other tissues and organs
permission, from data presented in (48). retain much of their mass and structure during a fast because

796 Volume 6, April 2016

Comprehensive Physiology Physiology of Fasting

(A) Clarius lazera (299). Similar relative losses of body mass have been observed
100
for ectotherms, though over a much greater fasting duration;
45% after 12 months for X. laevis, 35% after 13 months for
75
C. carpio, and 30% after 20 months for R. esculenta (202,221,
50 Bone
374). In some instances, fasting mass loss is relatively modest
Skin
Body mass
for ectotherms. The lungfishes P. annectens and P. aethiopicus
25
Gills
Skeletal muscle
lost only 6% of body mass during laboratory estivation in
GI tract mud over a 6-month period (291). Six and 8 weeks of fasting
Liver
0 Fat resulted, respectively, in no change in body mass for Atlantic
0 1 2 3 4 5 6 7 salmon and only an 8% loss of body mass for the salmon,
(B) Months of fasting O. kisutch (317, 518).
Whereas larger animals lose more absolute mass per day
100 Nerodia rhombifer of fasting, mass-specific daily loss of body mass (g kg−1 d−1 )
Relative change in mass (%)

is generally inversely related to body mass and greater for

75 smaller animals (Fig. 17). For example, fasting gray seal pups
(45.1 kg), harp seal pups (33.8 kg), mink (2.75 kg), white-tail
Stomach
50 Skin prairie dogs (0.98 kg), and Brant’s voles (0.061 kg) lose body
Muscle/bone
Body mass
mass at specific rates of 8.0, 11.5, 24, 56, and 73 g kg−1 d−1 ,
25 Liver
respectively (245,410,474,588,603). Similarly, adult emperor
Small intestine
Kidneys
Fat
penguins (37.7 kg), king penguin chicks (12.5 kg), elder ducks
0 (1.83 kg), great knots (0.22 kg), and kestrels (0.12 kg) lost
0 1 2 3 4 5 6
Months of fasting
body mass while fasting at specific rates of 6.2, 6.6, 12.3,
(C)
31.8, and 55.0 g kg−1 d−1 , respectively (Fig. 17) (31, 97, 309,
100 Rattus norvegicus 463, 508).
This trend is likewise evident for ectotherms (Fig. 17).
75 Maintained at 22 to 30◦ C, greater sirens (0.55 kg), dia-
mondback rattlesnakes (0.3 kg), mudskippers (0.02 kg),
50 Kidney and green anoles (0.0045 kg) lost mass when fasting at
Heart
Epididymal fat
rates of 0.82, 1.42, 5.95, and 11.6 g kg−1 d−1 , respectively
25 Body mass (216,329,353,360). With their lower mass-specific metabolic
Spleen
Liver rates and lower body temperatures, ectotherms lose mass at a
0 much slower rate while fasting than endotherms. The allomet-
0 1 2 3 4 5
Days of fasting ric scaling of mass loss is nearly identical among ectotherms,
birds, and mammals, however the Y-intercept for ectotherms
Figure 16 Relative change in body mass and individual organs and is 4.7% of those collectively for birds and mammals (Fig. 17).
tissues as a function of time fasting for (A) the fish Clarius lazera, (B) the Because daily rate of body mass loss varies among the
snake Nerodia rhombifer, and (C) the rat Rattus norvegicus. Compared
to the rate of body mass loss, individual organs and tissue lose mass three phases of fasting, this parameter is typically used to
at a lower or greater rate with time fasting. Figures for Clarius lazera distinguish the phases (Fig. 18). Characteristically, rate of
and Rattus norvegicus were drawn, with permission, respectively, from mass loss is high for phases I and III and lower during Phase II.
data presented in (242) and (218). Figure for Nerodia rhombifer was
drawn, with permission, from unpublished data of M. Larkin and S. For example, during the 6 to 9 days of Phase I fasting, king
Secor. penguin chicks lost 12 to 61 g kg−1 d−1 , a rate that was
reduced to 6.3 g kg−1 d−1 for the 133 days of Phase II, and
then increased to 21.2 g kg−1 d−1 following the transition to
they continue to function (e.g., skin, heart, and kidney) and Phase III (102). A similar profile were observed for laboratory
hence lose mass at a slower rate (Fig. 16). Absolute rates of rats; 92 g kg−1 d−1 for Phase I, 55 g kg−1 d−1 during Phase II,
body mass loss are dictated by body size, metabolic rate, and and increasing to 88 g kg−1 d−1 during Phase III (236).
the phase of fasting being experienced. Thus, the rate of mass
loss is highly variable among animals and for each may vary
Body fat
within the fast.
Significant declines in body mass are well documented for Fasting is characterized by a steady decline in body fat stores.
fasting endotherms. King penguin chicks starting at 10.35 kg Induced by hormones and other mediators, lipases within
lose 7.75 kg (75% of original mass) after 5 months of fasting adipocytes or other tissues (e.g., liver) cleave fatty acids from
(148). Five weeks of fasting resulted in the loss of 38% and the glycerol backbone (438). Fatty acids and glycerol are
41% of initial body mass for white-tailed and black-tailed then either oxidized locally or enter circulation. Adipocytes
prairie dogs, respectively (245). Male mallard ducks lose 52% thereby collectively shrink in size during the fast (Fig. 19A)
of body mass (from 2.98 kg to 1.43 kg) after 25 days of fasting (148). With fasting durations of 4 days, 12 days, 15 days,

Volume 6, April 2016 797

Physiology of Fasting Comprehensive Physiology

1000 1000
Mammals Mammals
Birds Birds Birds 21.38mass-0.375
Mammals 26.92mass-0.368
100

g kg–1 day–1
100

g day–1
10 10

Birds 21.38mass0.625
Mammals 26.92mass0.632
1 1
0.01 0.1 1 10 100 1000 0.01 0.1 1 10 100 1000

100 100
Ectotherms Ectotherms

1.12mass0.627 1.12mass-0.373
10

g kg–1 day–1
10
g day–1

1 1

0.1 0.1
0.001 0.01 0.1 1 10 0.001 0.01 0.1 1 10
Body mass (kg) Body mass (kg)

Figure 17 Absolute (g day−1 ) and mass specific (g kg−1 day−1 ) loss of body mass plotted against body
mass for birds, mammals, and ectotherms. Data were generated from studies that provided body mass
before and after a known period of fasting. Note the near identical allometric scaling exponents for birds,
mammals, and ectotherms.

2 weeks, 2 months, 2 months, 3 months, 4 months, and 6 salmon O. kisutch, raccoon dog, emperor penguin, estivat-
months, fat stores were reduced by 49%, 65%, 94%, 70%, ing lesser siren (S. intermedia), and the rattlesnake C. atrox
40%, 43%, 80%, 54%, and 56%, respectively, for the sable, (31, 207, 216, 316, 360, 390, 463). Daily rates of body fat loss,
green anole, laboratory rat, great knot (Calidris tenurostris), calculated from fat mass of individuals sampled at various
fasting durations, include estimates of 33 g day−1 for fasting
and molting rock hopper penguins, 125 g day−1 for fasting
(A) 80
harp seal pups, and 280 g day−1 for fasting gray seal pups
I II III (578, 588).
60 The fasting depletion of lipids is heterogeneous among
g kg–1d–1

body fat stores, a feature that varies among species. Over a

40 56-day fast, much of the fat loss for the raccoon dog origi-
nates from subcutaneous stores (depleted by 45%), followed
by intra-abdominal (omental, retroperitoneal, and mesen-
20
1 2 3 4 5 6 7 8 teric) fat stores that are depleted by 38% (Fig. 19B) (390).
(B) 30 Seven days of fasting is enough for mink to lose 14% of
their subcutaneous fat, while depleting intra-abdominal and
20 intermuscular fat stores by respective 38% and 36% (474).
g kg–1d–1

For the American martin, only 2 days of fasting leads to

44.3%, 48.7%, and 2.5% depletion of subcutaneous, intra-
10
abdominal, and intermuscular fat, respectively (Fig. 19C)
I III
II (408).
0 Mammals that hibernate experience dramatic changes in
0 10 20 30 40 50
body mass and lipid stores over the course of the annual cycle
Days of fasting
(126). During the active season, ground squirrels can double
Figure 18 Mass specific daily loss of body mass illustrated for the their body mass and increase fat mass by 2 to 3 times, depend-
three phases of fasting for (A) common barn owl (Tyto alba) and (B) ing on variables such as species, sex, reproductive condition,
breeding king penguin (Aptenodytes patagonica). Birds experienced and age (126, 197). Winter fasting leads to a reversal in these
greater specific mass loss during phases I and III of fasting compared
to phase II. Figures drawn, with permission, from data presented in patterns, with body mass and lipid stores falling to 40% to
(101, 241). 70% of prehibernation levels (18, 62, 197, 368).

798 Volume 6, April 2016

Comprehensive Physiology Physiology of Fasting

(A) Aptenodytes patagonicus (A)

Gastrocnemius
1.8

% of BM
1.2
NCA STF LTF 0.6
(B)
1800
0
Nyctereutes procyonoides
NCA STF LTF
1200 (B)
Fed
g

600 Fasted

Pectoralis
0 9
Martes americana

% of BM
(C) 9 6

3
6
0
NCA STF LTF
g

3
Figure 20 Electron micrographs of (A) gastrocnemius and (B) pec-
toralis muscle sampled from king penguin chicks (Aptenodytes patago-
nicus) following control feeding (NCA), 3 weeks of laboratory fasting
(STF), and several months of a natural fast (LTF) as presented in (148).
Below each set of micrographs is the relative mass (% of body mass) of
us

ric

ic

r
ta

ea

la
at
eo

en

te

cu
on

these muscles for each treatment. Note the loss of sarcomere integrity
m
en
an

us
ra

rit

following the natural fast (LTF) for both muscles, and the increase in rel-
O

es

rm
ph
ut

pe
M
bc

ia

te
ro

ative mass of the gastrocnemius but decrease in relative mass of the

D
Su

In
et
R

pectoralis with duration of the fast. Figures illustrating relative muscle

Figure 19 (A) Micrographs of intraperitoneal fat bodies from king
penguin chicks (Aptenodytes patagonicus) following control feeding
(NCA), three weeks of laboratory fasting (STF), and several months of a
natural fast (LTF) (148). Mass of regional fat deposits of fed (closed bars)
and fasted (open bars) (B) raccoon dog (Nyctereutes procyonoides) and
(C) American marten (Martes americana). Raccoon dogs and martens
had been fasted for 56 and 2 days, respectively. Illustrated is the char-
acteristic depletion of fat stores during fasting. Figures B and C were
drawn, with permission, from data presented in (390, 408).
Skeletal muscle
Skeletal muscles possess the largest source of labile proteins
within the body and thus lose mass during a fast as muscle
proteins are degraded and the released amino acids are catab-
olized, or channeled into gluconeogenesis. After 40 days of
fasting and experiencing Phase III fasting, domestic geese
have lost approximately 50% of their skeletal muscle mass
(322). Nordøy et al. used computed tomography (CT) to cal-
culate that harp seal pups lose 10.7% of skeletal muscle dur-
ing 23 days of a postwean fast (410). Nineteen days of fasting
resulted in a 11.7% loss of white muscle mass for the carp
C. carpio, whereas a 7-month fast lead to a 58.6% loss of
white muscle for the African catfish Clarius lazera (43, 242).
To evaluate fasting loss of muscle mass, studies often tar-
get specific muscles including leg (e.g., gastrocnemius) and
masses are drawn, with permission, from data presented in (148).
flight (e.g., pectoralis) muscles. Fasting durations of 5 days,
14 days, 3 months, and 18 months resulted in 22%, 13.6%,
54%, and 45% deceases in leg muscle wet mass for the rat,
great knot, king penguin chick, and frog R. esculenta, respec-
tively (31, 148, 218, 221). However, for the rat, great knot and
penguin chick, the relative loss of leg muscle mass was less
than total body mass loss; therefore, the relative masses (%
of body mass) of these leg muscles increased with fasting
(Fig. 20A). For fasting birds, the large pectoralis muscle is
a primary source of catabolized protein as demonstrated by
the 23.8%, 34%, and 95.2% loss in wet mass of this muscle
for the great knot, American eiders, and king penguin chicks
after 14 days, 24 days, and 3 months of fasting, respectively
(31, 148, 309). For these three birds, respectively, pectoralis
muscle loss occurred at a rate that was less than, equivalent
to, and greater than the rate of body mass loss (Fig. 20B).
Following months of fasting, the white axial muscles
of several fish species have been described as “jellied,”
due their jelly-like glossy appearance and quivering motion
when touched (545). This phenomenon, described for species
of flatfish (e.g., sole, plaice, and flounder) and cod, is

Volume 6, April 2016 799

Physiology of Fasting Comprehensive Physiology

characterized by a decrease in myofibrillary area and increases (A)

in interfibrillary space and water content (297, 336, 344, 545). 7500 Fall Spring 450
While other studies on fishes have documented the fasting

# fibers/3900 um2
degradation of the largely glycolytic white muscle fibers (not 5000 300
necessary “jellied”), they all found the size and integrity of

µm2
the aerobic red muscle to be well conserved with fasting
(297, 344, 428). Eighteen weeks of fasting for the Crucian 2500 150

carp Carassius carassius led to a 21% decrease in white mus-

cle myofibril surface area, but no change in myofibril coverage 0 0
fast slow density fast slow density
for the red muscle (428). Preserving red muscle allows fast-
Gastrocnemius Biceps femoris
ing fishes to maintain sustainable swimming performance,
whereas burst performance declines with the loss of white (B)
30 Fall/early denning Spring/late denning

CS activity (µmol g–1min–1)

muscle (344).

Contraction force (Nm)

For animals that are also inactive while fasting, skele-
tal muscle atrophy stems from protein degradation to fuel 20
metabolism as well as from disuse. Without constant stimu-
lus from activity, skeletal muscle cells shrink as rates of pro- 10
tein degradation exceed rates of protein synthesis (287, 479).
Thus, although hibernators and estivators would be expected
to be susceptible to both avenues of muscle loss, these species 0
Gastrocnemius Biceps femoris Tibialis anterior
typically show minimal or no loss of skeletal muscle integrity
(C) 120
compared to animals that do not normally undergo metabolic Early denning Late denning
depression. Reduced metabolism likely contributes to this
effect, as it reduces oxygen demand and thus oxidative stress 80
to all cells and tissues; however, in some cases specific mech-
ms

anisms that maintain skeletal muscle integrity have been iden-

tified in species that regularly experience periods of fasting
and inactivity (12, 200, 276, 325, 472, 592). The benefit of
preserving skeletal muscle structure and performance during
hibernation and estivation is that the animals are able to com-
mence foraging, mating, and predator avoidance immediately
upon arousal from dormancy.
Black and grizzly bears preserve skeletal muscle pro-
tein, fiber structure, and strength during winter hibernation
[reviewed in (244)]. Four months of hibernation had no effect
on the cross sectional area of either fast-twitch or slow-twitch
fibers in gastrocnemius and biceps femoris muscles (Fig. 21A)
(550). Hibernating black bears retain citrate synthase (CS)
activity of the gastrocnemius, but experience a 25% decline
in CS activity of the biceps femoris, and a 29% loss in max-
imum twitch force of the tibialis anterior muscle (Fig. 21B)
(331). However, for the tibialis anterior muscle, seven twitch
parameters including contraction time, half-relaxation time,
and peak rate of development did not change during hiberna-
tion (Fig. 21C) (331).
Minimization of skeletal muscle atrophy during hiberna-
tion has been well documented in smaller species such as
ground squirrels and prairie dogs (12, 115, 200, 265, 325, 413,
472, 473, 529, 577). The time dependence of skeletal mus-
cle dynamics over the course of the hibernation season was
examined for 13-lined ground squirrels using volumetric mag-
netic resonance imaging (MRI). Upper hindlimb muscle vol-
ume declined from summer to mid-winter, then reversed after
February such that volume rose significantly thereafter, even
though body mass continued to decline until April (265).
When normalized to prehibernation body mass, the mass of
40
0
Contraction Half-relaxtion Time to peak Time to peak
time time development decay
Figure 21 (A) mean cross-sectional area (blue) and density (red) of
fast- and slow-twitch muscle fibers in the gastrocnemius and biceps
femoris of black bears (Ursus americanus) prior to hibernation (fall,
open bars) and immediately following hibernation (spring, closed bars).
(B) Citrate synthase (CS) activity (blue) of gastrocnemius and biceps
femoris muscles and contraction force (red) of the tibialis anterior muscle
determined from bears sampled in the fall or early in hibernation (open
bars) and sampled in the spring or late in hibernation (closed bars). (C)
Twitch parameters of the tibialis anterior muscle for black bears mea-
sured early and late during hibernation. Illustrated is the lack of change
in muscle structure and function for black bears during hibernation. Fig-
ures drawn, with permission, from data presented in (331, 550).
the rectus femoris, biceps brachii, and gastrocnemius (but not
soleus) increased during the late hibernation period. Refeed-
ing in April restored muscle volumes to their prehiberna-
tion values. This apparent prioritization of skeletal muscle
regrowth prior to spring emergence is further demonstrated
by changes in rates of protein synthesis measured in squirrels
in early versus late winter. Compared with summer, protein
synthesis in mixed quadriceps samples is depressed by 66% in
early winter but returns to summer levels by late hibernation,
prior to refeeding. In contrast, no changes were observed in
protein synthesis rates in heart, liver or intestine among sum-
mer, early winter, and late winter squirrels (265).
Although cellular mechanisms responsible for main-
tenance of skeletal muscle mass and function during

800 Volume 6, April 2016

Comprehensive Physiology Physiology of Fasting

hibernation are still under investigation, likely candidates (A) 0.09

Control

Muscle dry mass (g)

include maintenance of slow myosin heavy-chain proteins
(472, 473), reduced myostatin levels (60, 61, 413), increased 9-month aestivation
0.06
antioxidants (6,288), activation of serum- and glucocorticoid-
inducible kinase 1 (12), and altered expression of various
transcription factors that regulate muscle growth and function 0.03
(546, 592).
In similar fashion, estivating anurans experience modest 0.00
losses of muscle mass and performance. Four months of
submerged hibernation (4◦ C) in the laboratory had no effects
(B) 300
on the mechanical properties of the locomotory and calling
muscles of the frog Rana temporaria (576). Maximum iso-

# Fibers mm–2
metric tetanic stress and power output of the external oblique 200
and sartorius muscles remain stable throughout this episodes
of laboratory-induced dormancy (576). Up to 6 and 9 months
100
of estivation had no effects on the mass of the locomotory
muscles, the gastrocnemius, sartorius, semimembranosus,
cruralis, and gracilis major for the Australian frog C. albogut- 0
tata. (Fig. 22A) (274, 276) Even after 9 months of estivation, (C) 240

Maximum stress twitch

the sartorius, cruralis, and iliofiularis muscles of this frog
were still well preserved in mass and morphology, whereas 160
the gastrocnemius experienced some loss in cross-sectional (kN m–2)
area (Fig. 22B) (542). Performance of the locomotory
muscles of C. alboguttata likewise did not diminish during 80
estivation as they maintained twitch forces and power output
after months of disuse (Fig. 22C and 22D) (274, 276, 542). 0
Estivating C. alboguttata appear to differentially regulate a
(D) 75
suite of genes involved in several major regulatory pathways
Peak power output

that may contribute to preservation of muscle function during

this period of immobility and food/water deprivation (446). 50
(W kg–1)

Bone 25

Fasting can compromise bone integrity due in part to the

absence of adequate calcium intake. As noted for skele-
tal muscle, disuse atrophy can compromise function when
inactivity accompanies prolonged fasting. Among hibernat-
ing mammals, bears have a remarkable ability to preserve
bone integrity during winter dormancy (365,366), and smaller
hibernators such as ground squirrels and marmots also pre-
serve bone structure during hibernation (364, 560, 587).
0
Gastrocnemius Iliofibularis Sartorius
Figure 22 (A) Muscle dry mass, (B) muscle fiber density, (C) maxi-
mum stress twitch, and (D) peak power output for the gastrocnemius,
iliofibularis, and sartorius muscles for control (fed and active) Cyclo-
rana alboguttata and following 9 months of aestivation. This frog did
not experience any loss in muscle mass or performance even after 9
months of aestivation. Figures drawn, with permission, from data pre-
sented in (348, 542).

Organs
As a function of their individual needs during fasting, of
providing metabolizable substrate during the fast, and their
capacity to rapidly restore prefasting phenotype, organs and
tissues vary considerably in how they respond to fasting and
refeeding. In short, most organs can be loosely categorized as
being quiescent during a fast and hence experience atrophy
and downregulation, or as remaining active and maintain-
ing structure and function throughout the fast. The former
category is exemplified by the gastrointestinal tract and asso-
ciated organs. In the absence of eating and digesting, organs
of the gastrointestinal tract (esophagus, stomach, small intes-
tine, and hindgut) are less active and engaged primarily in
maintaining ion and water homeostasis, serving as a source
of endocrine mediators, and maintaining a barrier separating
luminal compounds and microbes from the systemic environ-
ment. The activities of the pancreas, liver, and gall bladder
are also reduced during fasting due to the lack of neural stim-
uli activated by food intake and reduced nutrient absorption.
Tissues of the digestive system can experience considerable
phenotypic flexibility, undergoing large regulatory swings in
form and function with fasting and refeeding (327). The
latter category includes the heart, gills, lungs, and kidneys
whose constant function provides the necessary vascular per-
fusion, respiration, and nitrogenous waste removal that are

Volume 6, April 2016 801

Physiology of Fasting
still required during a fast (Fig. 16). The following describes
known changes in structure and function of individual organs
with fasting and refeeding.
Esophagus
The vertebrate esophagus serves chiefly as a conduit transport-
ing food from the mouth to the stomach (or intestine for fishes
that lack stomachs). However, many birds possess a crop or
ingulvies, a sac-like extension of the esophagus used to store
food (e.g., seeds and insects) before later passage of the meal
into the stomach (67). The crop is also used for food storage
before regurgitation of contents to nestlings. Snakes often
hold food in their esophagus because their prey in many cases
is longer than the snakes’ stomachs (40). Extreme cases occur
for ophiophagus snakes (snakes that eat other snakes) with
as much as 80% of the ingested snake meal positioned within
the esophagus at the start of digestion (285). The esophagus,
which varies in length from very short (e.g., fishes) to quite
long (e.g., snakes), is lined on its luminal surface with a single
layer of columnar epithelium that contains many mucus-
producing goblet cells (340). The mucus aids in meal passage
and protects the epithelium from refluxed gastric juices
(90, 333).
Likely stemming from its limited role in digestion, there
are only a handful accounts of how the esophagus responds
to fasting and refeeding. Cox and Secor (119) found no
variation in esophagus wet mass among diamondback water
snakes (Nerodia rhombifer) fasted for 30 days and exam-
ined at 0.5, 1, 2, 4, and 10 days following feeding. Bessler
and Secor (40) investigated the morphology and luminal pH
of the distal esophagus of 30-day fasted and recently-fed
Burmese pythons, diamondback water snakes, and African
house snakes (Lamprophis fulginosus). All three species expe-
rienced a slight acidification of the distal esophageal lumen
after feeding due to food occupying that site. That study
revealed pythons to experience a significant decrease in the
thickness of the smooth muscle layers of the esophagus with
feeding due to the high degree of stretching resulting from the
rat meal (40).
Stomach
Stomachs mechanically and chemically transform ingested
meals into a soup-like chyme prior to its passage into the
small intestine. In the absence of eating, the stomach may
experience atrophy and a downregulation of acid production.
Fasting-induced gastric atrophy (40%-64% decrease in mass)
has been documented following 1 to 6 months of estivation
for the anurans C. ornata, C. alboguttata, P. adspersus, and
S. holbrooki, and after 3 months of hibernation for the toad
Bufo spinulosus (120, 399, 487). Three days of fasting led
to a 21% reduction in gastric mass for laboratory rats (66).
During egg incubation, male and female lesser snow geese
experience respective 25% and 40% reductions in gizzard dry
802
Comprehensive Physiology
mass (15). For alpine marmots (Marmota marmota), stom-
ach length and mass are lowest when animals emerge from
hibernation in April, increase throughout the active season
and peak in September prior to hibernation (277). Fasting and
refeeding does not always affect stomach mass, as numerous
species of anurans and reptiles lack any change in the wet mass
of the stomach after a month of fasting, followed by refeed-
ing (422, 487, 493, 494). Fasting and refeeding can generate
changes at the ultrastructural level of the gastric epithelium
(257,602). For the oxyntopeptic cells of the Burmese python,
fasting leads to an accumulation of zymogen granules and the
development of a thick apical tubulovesicular system. Feed-
ing triggers the loss of zymogen granules, a reduction of
the tubulovesicular system, and the elongation of the luminal
membrane into digitations (257).
Vertebrates apparently exhibit two patterns of gastric
acid production with fasting. Mammals, birds, crocodilians,
lizards, anurans, some teleost fishes, and elasmobranchs main-
tain a basal level of HCl production between meals as evident
by low gastric pH’s measured during fasting bouts (Figs. 23A
and 23B) (161, 183, 204, 424, 425, 559, 599) (S. Secor, unpub-
lished observations). For hibernating groundhogs (Marmota
monax) and arctic ground squirrels, secretion of gastric juice
and mucus continues through the hibernation season, even, at
least for acid secretion in the groundhog, during torpor bouts
at body temperatures as low as 4◦ C (191,354). It is likely that
continued production of HCl between meals reduces bacte-
rial colonization within the stomach (539). However, there are
exceptions among these taxa during reproduction-associated
fasts. Male king penguins are able to store fish within their
stomachs for up to 3 weeks to feed newly hatched chicks by
reducing HCl production (luminal pH increases to 6) and gas-
tric motility (205). Female gastric brooding frogs (R. silus)
swallow their fertilized eggs or early-staged larva and brood
the eggs/larva in their stomach until they emerge through
the mouth following metamorphosis (110). The frog’s gastric
epithelium undergoes histological changes consistent with the
suppression of acid production, a process hypothesized to be
induced by prostaglandins that are secreted by the eggs or
larva (166, 554).
The second pattern, observed for teleost fishes, turtles,
and snakes, involves the cessation of acid production with
the emptying of the stomach and the subsequent elevation
of gastric luminal pH to neutrality (Figs. 23C and 23D)
(40,185,367,379,486,600). Burmese pythons cease acid pro-
duction even before the last remnants of the meal (mats of
hair) have exited the stomach (499). Feeding triggers the rapid
increase in HCl production that acidifies the gastric lumen
within 6 h (40,600). Given that the proteolytic enzyme pepsin
requires an acidic lumen to be activated (from pepsinogen),
pepsin activity is similarly regulated with fasting and feed-
ing (118, 600). Considering the high cost of HCl production
(stoichiometry of one ATP hydrolyzed per H+ pumped), the
selective advantage of this mode of HCl regulation is the
reduction in daily energy expenditure during long predicted
episodes of fasting (409, 445, 486).
Volume 6, April 2016
Comprehensive Physiology Physiology of Fasting

(A) (A)
9 100 Small intestinal mass
Canis familiaris
80

6 60
pH

40

3 20

Relative (%) to fed condition

0 (B)
100
0 18 36 54 72 Mucosal thickness
(B) 80
9
60
Triakis semifasciata 40
6
20
pH

0
3 (C)
100
Enterocyte volume
80
0
0 12 24 36 48 60
(C)
9 40
Sparus aurata
20

6 0
pH

0
0 6 12 18 24
(D)
9 Python molurus
Figure 24 Fasting-induced changes (relative to fed state) in (A)
small intestinal mass, (B) mucosal thickness, and (C) enterocyte vol-
6 ume for Micropterus salmoides, Cyclorana alboguttata, Pyxicephalus
adspersus, Chelydra serpentina, Heloderma suspectum, Python molu-
pH

rus, Nerodia rhombifer, Passer domesticus, and Ictidomys tridecemlin-

3 eatus. Noted is the condition and duration of the fast for each species.
All species experience a fasting reduction in small intestinal mass,
mucosal thickness, and enterocyte volume, however there is consider-
able variation in the extent of the reduction. Figures drawn, with per-
0 mission, from data presented in (71,92,104,119,131,328,496) and
0 48 96 144 192
(S. Secor and D. Crossley, unpublished data).
Hours

Figure 23 Gastric pH profile for the (A) dog (Canis familiaris),

(B) leopard shark (Triakis semifasciata), (C) white sea bream (Sparus
aurata), and (D) Burmese python (Python molurus). The downturn arrows
note the time of feeding and the upturn arrows note the time of gastric
emptying. For the dog and leopard shark, the stomach remains acidic
and experiences an increase in pH with feeding (due to the buffering
effects of the food). In contrast, the white sea bream and python main-
tain a near neutral gastric pH while fasting, experience a rapid drop
in pH during digestion, and then curtail acid production with the emp-
tying of the stomach. Figures are drawn, with permission, from data
presented in (424, 486, 599, 600).
Small intestine
Among digestive organs, the small intestine exhibits the
most dramatic phenotypic responses to fasting and refeeding
(Fig. 24A). The absence of enteral nutrients leads to atrophy
of the small intestinal mucosa (i.e., villi, crypts, and lamina
propria). This is due in part to the fasting-induced reduction
in local (epithelial) and neuroendocrine signals that promote
epithelial cell function and proliferation (294), and to the
reduction in luminal molecules, including those from dietary
and microbial sources that can stimulate mucosal growth
(416). Depending on species, fasting for as little as 24 h can
cause intestinal atrophy, due primarily to shortening of villi
and, to a lesser extent, crypts, with a coordinate reduction
in total mucosal mass (Fig. 24B) (202, 328, 491). Fasting-
induced intestinal atrophy can result from several events
including reductions in enterocyte volume (Fig. 24C) (113),
reduced rates of cell proliferation (294), and increased ente-
rocyte apoptosis (284). Fasting-induced gut atrophy is ener-
getically favorable, given the expense to maintain an active
and robust intestinal mucosa (70). Feeding rapidly restores
the intestinal epithelium by the combined responses of ente-
rocyte growth (hypertrophy) and increase in cell replication

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Physiology of Fasting
(hyperplasia) (9, 149, 257). The following studies document
the responses of intestinal morphology to fasting and refeed-
ing.
A 40-day fast for the Atlantic salmon led to respec-
tive mass losses of 50% and 38% for the pyloric cecae and
small intestine. Refeeding rapidly restored cecae mass, and
small intestine mass was restored by 35% after 7 days (311).
Two months into their winter fasting period, winter flounder
(P. americanus) had reduced mucosal mass and mucosa sur-
face area of their pyloric caeca and foregut by nearly 50%
(369). A similar 2-month fast reduced intestinal and mucosal
wet mass by respective 60% and 73% for the rainbow trout
(Salmo gairdneri) (44). Fasts of 14 and 16 days decreased
villus length by 25% and 52%, respectively, for the fishes
R. rutilus and Hyphessobrycon luetkenii (3, 203). The pyloric
caeca of fish likewise experience fasting-induced atrophy as
demonstrated by the respective 25% and 34% reduction in
enterocyte height and villus length following six weeks of
fasting for the Caspian salmon (Salmo trutta caspius) (152).
For mammalian hibernators, winter fasting leads to atro-
phy of the intestinal mucosa, particularly for fat-storing
species that do not consume food during periodic arousals
(71, 72, 76, 277). Mucosal atrophy begins shortly after food
intake is curtailed in the fall and is reflected by reductions
in villus length, crypt depth, and total mucosal surface area
(71, 72). These changes are due to reductions in enterocyte
DNA synthesis, mitotic activity, proliferation, and migration
from crypts to villus tips (188, 307, 563, 564). Overall, small
intestinal mass is reduced 50% to 75% for ground squir-
rels and marmots from mid-summer values (71, 76, 277).
Hibernation-induced gut atrophy does not appear to be due
to increased enterocyte apoptosis, although there are reports
that fasting in nonhibernating species can increase enterocyte
apoptosis due to oxidative damage (22, 284). Interestingly,
there is evidence for intestinal oxidative stress and increased
expression of some proapoptotic proteins during hibernation,
but the strong upregulation of several antiapoptotic, prosur-
vival pathways likely promotes a homeostatic balance in the
fasted gut (73, 177). The resumption of enterocyte prolifera-
tion and migration that occurs when body temperature rises
during each interbout arousal (74) may also help minimize
excessive atrophy as winter fasting progresses. For food-
storing hibernators such as the European hamster (Cricetus
cricetus) and garden dormouse (Eliomys quercinus), periodic
arousals are accompanied by feeding, which presumably is the
major factor that maintains the intestine closer to its normal
size in these species (196, 523).
Estivation ranging from 1 to 9 months for the anurans
C. alboguttata, C. ornate, P. adspersus, and S. holbrooki
resulted in 50% decreases in enterocyte volume, 35% to 75%
reductions in mucosal thickness, and 50% to 80% loss of
small intestinal mass, all restored with refeeding (Figs. 24A-
C) (120,487,496). Three and 5 months of hibernation resulted
in a 57% and 40% decrease in villus length for the toad B. spin-
ulosus and the frog R. temporaria, respectively (399, 504).
Compared to the fed state, after a 30-day fast enterocyte
804
Comprehensive Physiology
volume in the small intestine of the lizard H. suspectum
was reduced by 50%, resulting in a 35% decrease in villus
length (104). Small intestinal mass oscillates over a twofold
range with feeding and fasting for infrequently feeding snakes
(422,494). For several species of pythons, feeding reverses the
fasting-induced decrease (30%-50%) in enterocyte width and
mucosal thickness (422). For pythons, postprandial enterocyte
hypertrophy is also complemented by significant enterocyte
hyperplasia, both contributing to the rapid growth of their
intestines with refeeding (257).
To simulate a natural migratory fast and refeeding at stop-
over sites, blackcaps (Sylvia atricapilla) fasted for 2 days
experienced an 18% reduction in villus length and a 45%
loss of small intestinal mass; both responses fully reversed
after 2 days of feeding (302). When compared with feeding
birds prior to departure, migrating great knots (C. tenuirostris)
experienced a 42% reduction in intestinal mass and a 45%
reduction in body mass following a 4-day flight of 5400 km
from Australia to China (31). Similarly, great knots held in
captivity lost 64% of intestinal mass (and 45% of body mass)
after a 1-week fast (31). Following 5 days of Phase II fasting
in rats, intestinal mucosal mass fell by 52%, villus height
decreased by 30%, and rates of cellular proliferation were
reduced by 40%. An additional week of fasting reduced the
rat’s villus length to half its original length. Refeeding the
rats restored cell proliferation within 6 h, and villus height
and mucosal mass within 3 days (149, 236).
Two noted structural modifications associated with fasting
and feeding occur for the epithelium and microvilli. Fasting-
induced shortening of the intestinal villi is characterized by
a decrease in enterocyte thickness and the possible rear-
rangement of the epithelium into a pseudostratifed pattern
(328,399,422,527). In this configuration, enterocytes overlap
each other such that not all cells possess an apical exposure
to the lumen. With refeeding and enterocyte hypertrophy, the
cells are restored to their stratified columnar architecture, with
each cell’s apical end exposed to the lumen (422).
For ectotherms, fasting and refeeding can significantly
impact enterocyte microvillus length (202, 257). One, 5, and
6 months of fasting for the fishes, Silurus meridionalis,
Pterygoplichthy disjunctivus, and C. carpio, respectively, and
up to 3 months of estivation for the anurans C. albogut-
tata, C. ornate, P. adspersus, and S. holbrooki results in
28% to 60% reductions in microvillus length (Fig. 25)
(120, 202, 213, 487, 496, 602). More impressive are the 80%
reductions in microvillus length experienced by pythons after
1 month of fasting (Fig. 25) (498). With feeding, the python
microvilli double in length within 12 h, and double again
in length within 24 hours before peaking in length at day
3 of digestion (328). Within a week of the intestines being
cleared, the python microvilli have shortened by 70% (328).
For mammals, any fasting-induced changes in microvillus
length are much more modest (Fig. 25). For 13-lined ground
squirrels, hibernation has no effect on microvillus length and
actually increases microvillus density compared to summer
values (77). For hamsters and laboratory rats, 2 and 5 days
Volume 6, April 2016
Comprehensive Physiology Physiology of Fasting

Fed
Fast

100

75

% 50

25

0
Ictidomys Nerodia Ictalurus Pterygoplichthys Heloderma Ceratophrys Pyxicephalus Python
tridecemlineatus rhombifer punctatus disjunctivus suspectum ornata adspersus molurus

Figure 25 Electron micrographs of intestinal microvilli of fed and fasted 13-lined ground squirrel Ictidomys tridecemlineatus diamondback water
snake Nerodia rhombifer, channel catfish Ictalurus punctatus, vermiculated sailfin catfish Pterygoplichthys disjunctivus, Gila monster Heloderma
suspectum, South American horn frog Ceratophrys ornata, African bullfrog Pyxicephalus adspersus, and Burmese python Python molurus (77,
104, 119, 131, 213, 328, 496). Fasting conditions are respectively; 6-week hibernation, 30-day fast, 5-day fast, 150-day fast, 30-day fast,
1-month aestivation, 1-month aestivation, and 30-day fast. Below each set of micrographs is illustrated the relative change in microvillus length
with fasting.

of fasting reduced microvillus length by only 15% and 12%,
respectively (149, 376).
The fasting/refeeding morphological responses of the
intestine are associated with functional responses, chiefly
changes in nutrient uptake and hydrolase activities (172). Two
to 11 days of fasting reduced intestinal maltase and leucine
aminopeptidase activities for the salmon S. salar; a response
reversed after 7 days of refeeding (311). Twenty-four days
of fasting decreased intestinal aminopeptidase activity of the
catfish S. meridionalis by 50% (602). After 1 week of fasting,
channel catfish (Ictalurus punctatus) experienced a reduc-
tion in intestinal transport of L-leucine, L-proline, and D-
glucose (131). For the anurans Bufo alverius, C. ornata, and
P. adspersus a 2-week fast reduced intestinal nutrient transport
(Figs. 26C and 26D) (487). Compared to digesting individu-
als, toads (B. spinulosus) fasting for 2 weeks reduced intestinal
hydrolase activities (maltase, trehalase, and aminopeptidase)
by 50%, with a further reduction (20%-50%) experienced
after 3 months of hibernation (399). The binge-feeding lizard
H. suspectum and sit-and-wait foraging boas, pythons, and the
rattlesnake Crotalus cerastes all experience intestinal atrophy
and the downregulation of intestinal hydrolase activity and/or
nutrient uptake with fasting, and these responses are reversed
with refeeding (Fig. 26A-D) (104, 422, 494).
In contrast to a pattern of fasting-induced downregulation
of intestinal function, avian and mammalian intestines can
experience an increase in mass-specific activity with fasting.
A 1-day fast for house sparrows led to an increase in the
specific activities (i.e., per gram of intestine) of the hydro-
lases aminopeptidase and sucrase (92). During hibernation,
13-lined ground squirrels experience an increase in the spe-
cific activities of nutrient transporters (Figs. 26C and 26D)
(71,76,77). In both instances, it appears that enterocytes from
fasted animals retain or even increase activity of hydrolytic
enzymes and nutrient transporters, which may be an adap-
tive response to the overall loss of mucosal mass induced by
fasting. It is important to note that fasting-related changes in
intestinal function are not ubiquitous among animals; many
exhibit no significant changes. For instance, a week of fast-
ing had no impact on the activities of intestinal hydrolases
or nutrient transporters for grass carp (Ctenopharyngodon
idella) (Figs. 26A-D) (131). Two weeks of fasting failed to
induce any change in small intestinal nutrient uptake for the
anurans B. marinus, Leptodactylus pentadactylus, and Rana
catesbeiana (487). Compared to fed individuals, 1-month of
fasting had no effect on intestinal nutrient uptake for the turtles
Chelydra serpentina, Sternotherus odoratus, and Trachemys
scripta, the alligator Alligator mississippiensis, and the snakes
Coluber constrictor, Masticophis flagellum, N. rhombifer, and
Pituophis melanoleucus (Figs. 26A-D) (119, 214, 493, 494).
Variations in the intestinal response in form and function
to fasting and refeeding may be adaptively linked to natural
feeding habits. For example, snake species that feed fre-
quently in the wild experience only modest changes in intesti-
nal morphology after fasting/refeeding and no significant reg-
ulatory swings in intestinal function (487). In contrast, snakes
that feed infrequently and experience long intervals between
meals exhibit greater morphological changes and significant
regulation of intestinal function with each fasting/refeeding
episode (487). For snakes (at least), the modulation of
intestinal microvillus length appears to be the chief cellular

Volume 6, April 2016 805

Physiology of Fasting Comprehensive Physiology

200 (A) Aminopeptidase Large intestine and cecum

150 The relatively few studies that have examined how the hindgut
100
(cecum and large intestine) responds to fasting and refeeding
report variable effects on tissue mass, and where effects are
50 noted they are generally of lesser magnitude compared with
0 the small intestine. Fasts of 2 weeks for 6 anuran species and
300 (B) of 1 month for 13 species of snakes resulted in no change in
Maltase/sucrase
large intestinal mass (119, 422, 487, 494). However, as much
200 as a 50% loss of large intestinal mass was noted after 1, 1, and
Relative (%) to fed condition

9 months of estivation, respectively, for the anurans C. ornata,

100
0 following feeding (S. Secor, unpublished data).
200 (C)
D-glucose uptake
150
100
50
0
450 (D)
L-Proline uptake
300
150
0 the proliferative response. Metabolomic analysis suggested
Figure 26 Fasting generated changes (relative to fed state) in small
intestinal (A) aminopeptidase activity, (B) maltase or sucrase activ-
ity, (C) D-glucose uptake, and (D) L-proline uptake for Ctenopharyn-
godon idella, Ceratophrys ornata, Amphiuma tridactylum, Chelydra
serpentina, Heloderma suspectum, Python molurus, Nerodia rhombifer,
Passer domesticus, and Ictidomys tridecemlineatus. Noted is the condi-
tion and duration of the fast for each species. Among these species,
there is considerable variation in magnitude by which intestinal func-
tion is regulated with fasting, ranging from sever downregulation, to
no change, to significant increases in mass-specific function. Figures
drawn, with permission, from data presented in (71,92,104,118,119,
131, 491, 496) and (S. Secor and D. Crossley, unpublished data; S.
Secor and M. Smith, unpublished data).
mechanism responsible for the regulation of intestinal
function. For frequently feeding snakes, microvillus length
and hence microvillus surface area do not vary between
meals, whereas infrequently feeding snakes increase and
decrease microvillus length with onset and termination of a
fast, respectively (118,119,498). For these snakes, changes in
microvillus surface area closely match the alteration in intesti-
nal function (Fig. 27A). A similar form-function relationship
was observed for the catfish S. meridionalis; after 24 days
of fasting they experienced a 43% decrease in microvillus
surface area and a 49% reduction in aminopeptidase activity
(Fig. 27B) (602).
P. adspersus, and C. alboguttata (120, 487, 496). The python
cecum undergoes no change in wet mass over a 30-day span
For rats, colonic cell proliferation decreases during a 36-h
fast and rapidly resumes upon refeeding (416). Within 6 h
of refeeding, cell proliferation rates had returned to control
(fed) values, after which rates continued to increase to peak at
24 h, before returning to control levels after 76 h of refeeding
(416). Colonic mucosal thickness however remained constant
with refeeding possibly due to the increase in proliferation
being balanced by an increase in cellular apoptosis (416).
In contrast, an increase in proliferation of colonic cells was
absent when the refeeding diet contained low levels of fer-
mentable carbohydrates (i.e., fiber) or for rats treated with oral
antibiotics, suggesting a role for the microbiota in mediating
that the bacterial metabolite lactate, produced by commen-
sal lactobacilli, was the most likely candidate responsible for
triggering proliferation (416).
The effects of winter fasting on hindgut structure and
function in mammalian hibernators have been explored in
marmots and ground squirrels. In alpine marmots, as is the
case for their small intestine, the masses of hindgut segments
are highest in late summer and lowest at the end of hiberna-
tion (277). One interesting difference is that whereas small
intestinal mass falls from mid (July) to late summer (Septem-
ber), presumably due to a gradual reduction in food intake,
mass of hindgut segments remain at their highest levels. In
ground squirrels, crypt lengths in the cecum fall progressively
with time in hibernation, from a high in summer through 1
and 4 months of winter fasting. Two weeks after refeeding in
spring, crypt length is greater than in hibernation but is still
reduced compared with summer values (144).
Brain/Nervous system
Compared with many other organs, the central nervous system
is relatively resistant to fasting-induced reductions in tissue
mass. Brain wet mass did not change after 7 days of fast-
ing for the laboratory rat (which lost 27% in body mass) or
after 42 days of fasting for the Atlantic salmon (518). Follow-
ing 6 months of laboratory-induced estivation, C. alboguttata
exhibited no change in the shape of neuromuscular junctions,
in resting membrane potential of muscle fibers, or in miniature
end plate potential frequency and amplitude. These frogs did

806 Volume 6, April 2016

Comprehensive Physiology Physiology of Fasting

Python molurus
(A) 1.5 3.2

(nmol min–1 mg–1)

2.4

L-Proline uptake
MVSA (μm2)
1.0

1.6
Proline
0.5
0.8
MVSA

0.0 0.0
0 6 12 18 24 30
Days of fasting

Silurus meridionalis
(B) 2.4 24

Aminopeptidase activity
MVSA (μm2 μm–1)

MVSA
1.6 16

(U g–1)
AOP
0.8 8

0.0 0
0 8 16 24 32
Days of fasting

Figure 27 Correspondence between temporal changes in microvillus surface area

(MVSA, black) and intestinal function (blue) with fasting for (A) the Burmese python (Python
molurus) and (B) the southern catfish (Silurus meridionalis). In this figure, MVSA is com-
pared with L-proline uptake rates for P. molurus and with aminopeptidase activity for S.
meridionalis. Electron micrographs of intestinal microvilli at each time point demonstrate the
fasting-related shortening of the microvilli and hence decrease in MVSA. Micrographs and
the data used to make figures originate, with permission, from (119, 328, 602).

experience significant decreases in the amplitude of end plate
potential and increases in the proportion of nerve simulation
that failed to evoke end plate potentials (275).
Gills/Lungs
Gills and lungs generally maintain their size and integrity dur-
ing extended bouts of fasting, due largely to their continued
need for respiration. Lung wet and dry masses do not differ
between fasted (2-4 weeks) and recently fed anurans, turtles,
and snakes (119, 422, 487, 493, 494). For laboratory rats, a
7-day fast generated a 27% decrease in body mass, with a
modest 5% loss in lung mass (91). Four days of continuous
flying resulted in an estimated 48% loss in body mass with
only a 15% decrease in lung mass for great knots (31). These
birds preserve lung mass (and hence lung performance) dur-
ing migration relative to other organs; however a 1-week fast
in captivity resulted in loss of lung mass that was proportional
to body mass loss (31). Bouts of estivation can lead to noted
changes in gill/lung structure due to the absence of water and
change in use. Gills of estivating lungfishes adhere to each
other and the interlamellar spaces fill with mucus, while the
gills of estivating greater (S. lacertina) and lesser (S. interme-
dia) sirens decrease in ramus length (160, 207, 537). Lungs
of estivating lungfish increase function with an expansion of
surface area and vascularization (537).
Heart
There is little evidence for significant changes in heart mass
with fasting or after refeeding that are independent of changes
in body mass, or when body mass is controlled for among fed
and fasted treatments (31, 91, 221, 299, 408, 422, 487, 494).
Exceptions include a 24% decrease in heart mass (body mass
dropped by 17%) for house sparrows after 31 to 34 h of fast-
ing and as much a 40% increase in heart mass with refeeding
for the Burmese python (11, 92, 459, 491). The postprandial
growth of the python’s heart stems from cellular hypertrophy
(no evidence of hyperplasia) and apparently serves to increase
cardiac output to meet the elevated metabolic demands of the

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Physiology of Fasting Comprehensive Physiology

2.5 (A) Heart active gut (459, 488, 500). With fasting, the python’s heart
experiences atrophy as metabolic demands of digestion are
suppressed (500). Laboratory-induced estivation generates
2.0 changes in the structure of the ventricular myocardium of
the African lungfish P. dolloi (280). For estivating lungfishes,
1.5 cardiomyocytes increase in volume and double in sarcomere
length, while experiencing an increase in mitochondrial size
with a decrease in mitochondrial density. These changes are
1.0
reversed within 6 days after returning to water (280). When
20 (B) Liver
P. aethiopicus is induced to estivate in either mud or within
a bag, heart rate and blood pressure decrease by as much as
15 40% (135,176). After 16 weeks of laboratory estivation, heart
rate in the lesser siren (S. intermedia) was reduced by 50%
(207).
10
Echocardiographic images revealed no changes in left
ventricular wall thickness after a 5-month hibernation period
5 for black bears (319), however hibernating grizzly bears did
6 (C) Gall bladder experience a reduction in left ventricular mass (402). Ventric-
ular mass increased about 20% after 6 months of hibernation
for golden-mantled ground squirrels (577). This may be due
Wet mass (g)

4
in part to the increase accumulation of lipid droplets in the
cardiomyocytes of the hibernating squirrels compared to non-
2 hibernating ground squirrels (65).

0 Liver
8 (D) Pancreas
600 Amylase capacity For some species, the liver can match the small intestine in
μmol min–1

400 the magnitude of reversible plasticity experienced with fast-

6 200 ing and refeeding. Sixteen days of fasting for the fishes S.
0 meridionalis and H. luetkenii led to respectively 10.5% and
0 10 20 30
Days of fasting 13.3% loss in body mass, with concurrent 31% and 37%
4
decreases in liver mass (203, 602). For S. meridionalis, hepa-
tocyte volume was reduced by 41% (602). Decreases of 30%
2 to 76% of liver mass following 5 to 7 weeks of fasting have
(E) Kidneys been documented for the fishes C. lazera, Hopilias malabar-
1.6
icus, P. flavescens, and S. salar (184, 242, 458, 518). Eels
(A. anguilla) fasted for 20 weeks lost 21% of their body mass
1.2 while experiencing a 34% decrease in liver wet mass (318).
Experimental fasts of 1, 2, 12, and 20 months resulted in
0.8 40%, 40%, 30%, and 70% reductions, respectively, in liver
masses for the anurans C. ornata, S. holbrooki, X. laevis, and
R. esculenta (221, 374, 487). Compared to digesting toads
0.4 (B. spinulosus), individuals fasted for 2 weeks in the labo-
0 10 20 30
ratory and those following 3 months of natural hibernation
Days of fasting
lost a respective 11% and 40% of liver mass (399). Rep-
Figure 28 Fasting related change in wet mass of the (A) heart, (b) tiles likewise experience significant losses in liver mass with
liver, (C) gall bladder, (D) pancreas, and (E) kidneys for the Burmese extended fasting; 3 and 5 months of fasting led to reduc-
python (Python molurus). Time zero (0) represents the time point post- tions in liver mass of 44% and 28% for the broad nose caiman
feeding (2 or 3 days) that each organ was at its maximum (heart, liver,
pancreas, and kidneys) or minimum (gall bladder) mass. The insert for (Caiman latirostris) and the western diamondback rattlesnake
(D) illustrates the decline with fasting of pancreas’ capacity for amylase (C. atrox) (359,528), respectively. Refeeding reverses the loss
activity. Figures drawn, with permission, from data presented in (119) of liver mass; 2 days of meal digestion following a 30-day fast
and (S. Secor, unpublished data).
resulted in 40% to 85% increases in liver mass for pythons,
boas, and the sidewinder rattlesnake (422,494). However, not
all reptiles experience significant shifts in liver mass with fast-
ing and refeeding. In similar studies, refeeding after a 30-day
fast did not affect liver mass for the turtles, C. serpentina, S.

808 Volume 6, April 2016

Comprehensive Physiology
odoratus, and T. scripta, nor for several species of colubrid
snakes (119, 493, 494).
Fasting can also induce rapid losses in liver mass for birds
and mammals. Fasts of 34, 48, and 72 h, respectively, for the
house sparrow, American marten, and laboratory rat resulted
in 47%, 27%, and 42% reductions in liver mass, while these
animals only lost 17%, 13.5%, and 20% of their respective
body masses (66, 92, 408). Great knots lost approximately
40% of liver mass during 4 days of a nonstop migratory flight,
while losing 43% of body mass (31). Over longer fasting
episodes (25-30 days), mallard ducks and lesser snow geese
lose 57% to 69% of liver mass while experiencing 42-48%
reductions in body mass (15, 299). Assessed by volumet-
ric MRI, liver volume of 13-lined ground squirrels showed
a nonsignificant trend for reduced volume from late sum-
mer (September) to late hibernation (February) prior to the
resumption of feeding, but no change when volume was nor-
malized to body mass (which dropped by ∼40%) (265). King
penguin chicks fasted for 4 months lose 75% of body mass
and a concomitant 61% decrease in liver mass (148).
Gall bladder
For those species that possess one, feeding stimulates con-
traction of the gall bladder smooth muscle and relaxation of
the Sphincter of Oddi, which propels bile into the small intes-
tine to aid in emulsification of dietary lipids. In contrast to the
other organs of digestion, the gall bladder increases in volume
with fasting as bile continually produced by the liver accu-
mulates in the gall bladder lumen. Fasting can therefore lead
to as much as fourfold increase in gall bladder wet weight, as
documented for anurans and snakes (422,487), due to changes
in bile volume, rather than an increase in tissue mass.
Pancreas
The pancreas serves both exocrine and endocrine roles; the
former by secreting into the proximal small intestine diges-
tive enzymes and a bicarbonate-rich fluid to neutralize gastric
acid, and the latter by releasing hormones (chiefly insulin and
glucagon) into circulation. The exocrine acinar cells of the
pancreas make up >95% of pancreatic mass; therefore, fast-
ing might be predicted to result in reduced acinar cell mass
and function. The few studies that have explored fasting and
refeeding responses of the pancreas have reported a mixture of
responses. Refeeding after a month of fasting generated sig-
nificant increases in pancreatic mass for the anurans C. ornata,
and P. adspersus and the snakes Python brongersmai, P. molu-
rus, and N. rhombifer (118, 119, 422, 487). However, similar
treatments had no effects on pancreatic mass for other anu-
rans (e.g., B. marinus and R. catesbeiana) and snakes (e.g.,
Python regius, C. constrictor, C. cerates), or for turtles (e.g.,
C. serpentine and T. scripta) (422, 487, 493, 494). One, 2,
and 2 days of fasting generated respective 21%, 29%, and
8% decreases in pancreatic wet mass for the house sparrow
(Passer domesticus), blackcap, and American marten (92,302,
Volume 6, April 2016
Physiology of Fasting
408). A week into egg incubation, female and male lesser
snow geese had lost 30% and 45% of pancreatic mass, respec-
tively (15). Hibernation reduces pancreatic mass by 57% for
golden-mantled ground squirrels (33) and total pancreatic pro-
tein content by 50% for bats (32).
Like pancreatic mass, fasting and refeeding responses of
pancreatic enzyme function is variable. Fasting durations of
3, 5, and 7 days each led to decreases in trypsin and chy-
motrypsin activities that were rapidly restored with refeeding
for the fish Oreochromis mossambicus (89). Sixteen days of
fasting reduced trypsin and lipase activity by 40% for the
catfish S. meridionalis, but had no effect on amylase activity
(602). In contrast, even 3 weeks of fasting failed to elicit sig-
nificant changes in trypsin and chymotrypsin activities for the
fish Rutilus rutilus; however, this fish did experience a 50%
decrease in amylase activity that was reversed with feeding
(3). Fasting and refeeding effects on pancreatic function were
evident for P. molurus; after 1 month fast, feeding induced
respective 5.7- and 20-fold increases in the activities of pan-
creatic trypsin and amylase (118). During hibernation, non-
lactating black bears experience an 87% decline in pancreatic
lipase activity (323). The specific activity and protein expres-
sion of pancreatic amylase are reduced by 40% to 50% during
hibernation for 13-lined ground squirrels (25).
Spleen
Functioning in the filtration of blood, as a reserve of blood
cells, and in active immunity, the spleen tends to exhibit no
change in mass (independent of the change in body mass)
with fasting and refeeding. Fasting had no impact on spleen
mass for six anuran and five python species (422, 487). The
27% decrease in spleen mass for laboratory rats following
a 7-day fast nearly matched the 27% decrease experienced
in body mass (91). A unique response was observed for the
American marten which, after only a 2-day fast, experienced
a 48% decrease in spleen mass while body mass fell by only
13.5% (408).
Kidneys
Compared with other organs, kidneys are generally less flex-
ible in terms of morphological changes with fasting and
refeeding. Jordan [1953] noted a 45% reduction in body mass
of mallard ducks after 25 days of fasting, but more modest
decreases in kidney mass of 15% and 27% for female and male
ducks, respectively (299). Two to 10 days of fasting caused
no changes in kidney mass relative to body mass loss for the
American marten and laboratory rat (66,218,408). When nor-
malized to body mass, kidney volume (by MRI) in 13-lined
ground squirrels did not vary throughout hibernation, but vol-
ume normalized to body mass increased from late hibernation
(February) to spring (April) after refeeding (265). Following
2 to 4 weeks of fasting, refeeding failed to elicit any increase
in kidney mass for the anurans B. marinus, L. pentadactylus,
809
Physiology of Fasting
and R. catesbeiana, the lizard H. suspectrum, and snakes of
the genera Coluber, Lampropeltis, Masticophis, and Nerodia
(104,487,494). In contrast, fasts of 2, 4, and 7 months caused
respective losses of 47%, 50%, and 73% of kidney mass for
the fish C. lazera while the fish themselves lost, respectively,
19%, 35%, and 47% of their body mass (242). When normal-
ized to body mass, refeeding for 2 days after an extended fast
(>30 days) induced 33% to 92% increases in kidney mass for
the anurans B. spinulosus, C. ornata and P. adspersus, and
several species of boas and pythons (399, 422, 487, 494).
Gut microbes in fasting and refeeding
The microbial communities (“microbiota”) that reside in and
on animal bodies have diverse and often profound effects
on multiple aspects of host biology, from birth until death
(215, 363). For most animals, the gastrointestinal tract is the
site of highest densities of commensal microbes where they
can number in the trillions in some species, vastly outnumber-
ing host cells by 10 to 1 (591). Gut microbes form ecosystems
characterized by complex interactions with the host and with
each other. Dietary components that escape host digestion and
absorption provide ample substrates for microbial growth,
although endogenous substrates such as mucin glycans and
nutrients in sloughed epithelial cells can also be metabolized
by some species. Host diet is a major factor that influences
the abundance and composition of the gut microbiota as well
as the functional capacity of the microbiome (i.e., the com-
bination of microbial species and their respective genomes)
(130, 387). The composition of the host diet influences the
types of metabolites produced by gut microbes, and since
many of these are now known to act as signaling molecules
among microbes and between microbes and the host, diet
composition can affect many aspects of host physiology via
processing by the microbiota (146, 509). Given these consid-
erations, it is not surprising that anticipated or unanticipated
episodes of fasting and refeeding affect the abundance, com-
position, and activities of the gut microbiota, and thus the
functional impact of microbes on fasting biology.
Short chain fatty acids (SCFAs) produced by gut
microbiota—including the three most abundant SCFA,
acetate, propionate and butyrate—can contribute between 5%
and 25% of the energy requirements of nonruminant animals
(37). This energetic benefit to the host may be particularly
beneficial under fasted conditions. For example, compared to
germ-free mice, mice with a normal gut microbiota are better
able to increase hepatic ketogenesis and maintain myocardial
energy oxidation and cardiac mass under fasted conditions
(121).
The involvement of gut microbes and their metabolic by-
products in the intestinal response to fasting and refeeding was
demonstrated in laboratory rats that were fasted for 36 h and
then refed for varying lengths of time up to 76 h (416). Cell
proliferation in the colon was reduced after 36 h of fasting,
810
Comprehensive Physiology
and the hyperproliferative response that occurs upon refeed-
ing in normal, chow-fed rats was abolished when dietary fiber
was removed from the diet, or when the experiment was car-
ried out using germ-free animals. Thus, a bacterial metabolite
appeared to be necessary for the refeeding response, which
the authors identified as lactate (416).
How gut microbial communities respond to periods of
fasting and refeeding of their hosts has been examined for
animals that naturally undergo changes in food intake as
part of their lifestyles. For the Burmese python, fasting
results in a dramatic reduction in the diversity of the micro-
biota in the large intestine (113). For fasting pythons, the
gut is dominated by members of the phylum Bacteroidetes
(Bacteroides, Rikenella), Proteobacteria, Firmicutes, Verru-
comicrobia (Akkermansia), and Deferribacteres (Synergistes).
Several of these, including Bacteroides thetaiotaomicron
and Akkermansia muciniphia, are able to degrade intesti-
nal mucins and subsist on the derived glycans as their sole
energy source, thus allowing them to flourish in the fasted
gut. (140, 521). Feeding is followed by a large expansion
in the diversity of the intestinal microbiota, most notably
by members of the phylum Firmicutes including the fam-
ily Peptostreptococcaceae and the genera Lactobacillus and
Clostridium. This rapid alteration in the microbiota is presum-
ably driven by the appearance in the large intestine of metab-
olizable components of the partially digested meal. The post-
prandial dominance of Firmicutes is mirrored by a reciprocal
decrease in the contribution of the Bacteroidetes to the micro-
bial community (Fig. 29). Upon the completion of digestion
(10 days postfeeding), the relative contributions of these two
dominate phyla to the python’s microbiota return to fasting
levels (roughly 50:50) (113).
The strong influence of host diet on shaping microbiota
composition is also seen in mammalian hibernators that fast
during the winter months (485). Compared with the micro-
biota of summer animals, phylogenetic diversity of the cecal
luminal microbiota (i.e., bacteria associated with bulk con-
tents in the lumen) decreases during hibernation for 13-lined
and arctic ground squirrels (78, 530) and in 13-lined ground
squirrels, diversity increases with the resumption of feeding
in the spring (78). For both ground squirrels, the relative
abundance of the phyla Bacteroidetes and Verrucomicrobia
increase during hibernation whereas the relative abundance
of several taxa in the Firmicutes phylum are reduced (78,530)
(Fig. 29). These changes likely reflect the better competitive
ability of taxa that contain species that are capable of surviving
on host-derived substrates, such as mucin glycans (140, 521)
compared with those that tend to prefer dietary polysaccha-
rides (many Firmicutes). Interestingly, these changes are not
seen in all species that hibernate; for example, in Syrian ham-
sters, hibernation had no effect on numbers or taxonomic
diversity of cecal luminal microbes relative to nonhibernating
hamsters (522). In contrast to ground squirrels, Syrian ham-
sters feed periodically during the hibernation season, which
Volume 6, April 2016
Comprehensive Physiology Physiology of Fasting

(A) 100

80 Firmicutes

Percentages of sequences
60

40

20
Bacteroidetes

0
0 2 4 6 8 10
Days postfeeding
(B)
100

80 Tenericutes
Percentages of sequences

Proteobacteria
60
Unclassified

40 Verrucomicrobiota

Firmicutes
20
Bacteroidetes

0
Summer Early Late Spring
active Winter hibernation active

Figure 29 (A) Postprandial separation of the relative percentages of the microbiota phylums
Bacteroidetes and Firmicutes within the large intestine for the Burmese python (Python molu-
rus). Within hours of feeding, Firmicutes come to dominate the microbiota community, while
the contribution of Bacteroidetes is greatly depressed. With the clearing of the intestine and
through fasting, both phyla then contribute equally to the microbiota community. (B). The rel-
ative abundance of microbiota phyla in cecal contents of 13-line ground squirrels (Ictidomys
tridecemlineatus) during summer activity, early and late winter hibernation, and spring activity
2 weeks postfeeding. Note the shifts with hibernation of the phyla Bacteroidetes, Firmicutes,
and Verrucomicrobia. Figures drawn, with permission, from data presented in (78, 113).

may be responsible for maintenance of their microbial popu-
lations similar to the active season configuration.
The mucosa-associated microbiota is also affected by
fasting and refeeding cycles in 13-lined ground squirrels. This
community, which is closely associated with the mucus layer,
is thought to be more resistant to perturbations such as those
induced by fasting and refeeding (483). Like the luminal
community, the mucosal microbiota undergoes similar sea-
sonal shifts over the hibernation cycle, although differences in
relative abundance of specific taxa are less pronounced (144).
The relative persistence of bacterial taxa within the squirrel
mucosal microbiota across the annual cycle, along with a
core assemblage of operational taxonomic units (analogous
to species) that makes up 36% to 76% of total sequences in all
animals regardless of season suggest that the relative stability
of this community is made possible because of continued host
production of their main energy source, mucin glycans (144).
Relative to summer squirrels, protein expression of the main
intestinal mucin, MUC2, is greater in squirrels after 1 month
of hibernation and in spring after two weeks of refeeding, and
expression levels were unchanged even after 4 to 5 months of
hibernation (144).

Volume 6, April 2016 811

Physiology of Fasting Comprehensive Physiology

The contribution of gut microbes to host protein bal- Integrating the molecular mechanisms of fasting
ance has been recognized for decades, particularly in foregut-
Recent complements to the numerous ecological, behavioral,
fermenting species. Urea that diffuses from the blood into
and physiological studies of fasting responses are studies that
the gut lumen is a nitrogen source for gut microbes; up to
take a molecular approach to exploring the integrative mech-
50% of host urea can be hydrolyzed in the hindgut by ure-
anisms underlying specific fasting phenotypes. The emer-
olytic bacteria, producing CO2 and ammonia (566) (see sec-
gence of these studies began in the 1990s with a focus on
tion on “Substrate utilization during fasting: Hibernation”).
hibernation, and employed methods of in situ hybridization,
Recycling of urea nitrogen by rumen microbes is crucial for
Northern blot analysis, and differential display to demon-
protein balance in ruminant species, but there is evidence that
strate the differential expression of genes between summer-
urea nitrogen salvage by hindgut microbes may contribute to
active and winter-hibernating animals (chiefly ground squir-
nitrogen conservation in nonruminants, especially if diets are
rels) (14, 56, 74, 164, 414, 524). An in situ hybridization study
low in protein or the animals are fasted or malnourished (513).
on Chinook and coho salmon published in 1998 identified
Urea nitrogen salvage has been proposed as a mechanism by
significant increases in signaling for neuropeptide Y (NPY)
which mammalian hibernators conserve protein during win-
in the preotic area of the hypothalamus for 3-week fasted fish
ter fasting (244, 405, 456). However, apart from a preliminary
(512). Given the current exponential increase in molecular-
report (244), studies that demonstrate bacterial urea hydroly-
based studies and the exhaustive amount of data being gener-
sis and appearance of the liberated nitrogen in amino acids or
ated, we highlight the chronology of these studies and review
proteins of the hibernator host are lacking.
three studies from different fasting biologies.
Other studies have examined microbiota changes in
Beginning in the 1990s, the examination of fasting-related
species that may experience periods of short-term or pro-
changes in gene expression shifted to microarray analysis,
longed starvation that are not associated with normal feeding
suppression subtractive hybridization (SSH), and quantitative
cycles intrinsic to the life history of the animals. An 8-day
real-time PCR (RT-PCR, qPCR). Investigators frequently cou-
fast lead to a substantial increase in the relative abundance
ple RT-PCR with other approaches (e.g., microarray, SSH, and
of bacteria of the phylum Bacteroidetes (from 8.2% to 36%)
RNAseq) to validate the direction and magnitude of expres-
within the intestine of the Asian seabass, Lates calcarifer
sion change for a targeted set of genes (169, 334, 451, 580).
(590). Contributing to this increase were elevated abundances
Microarray technologies identified hundreds of genes that
of members of the classes Bacteroidia and Sphingobacteria. In
were differentially expressed with fasting and refeeding in
contrast, the class Betaproteobacteria was reduced by fasting.
the axial muscle of the rainbow trout (451). Loong et al.
As noted earlier, several taxa within the class Bacteroides are
(334) used SSH to isolate genes in the liver that were dif-
particularly adept at harvesting alternative energy sources in
ferentially expressed between fasted-control and laboratory-
the intestine during a fast compared to other major bacterial
estivated African lungfish (P. annectens). For estivating lung-
groups. In fed seabass, Proteobacteria and Firmicutes were
fish, expression of genes related to urea synthesis and lipid
the most abundant phyla in the intestine whereas Proteobac-
metabolism increased, whereas genes involved in carbohy-
teria and Bacteroidetes were the dominant phyla after fasting.
drate and amino acid metabolism decreased.
The observed shift in the ratio of Firmicutes:Bacteroidetes
The targeting of liver genes in the Nile tilapia using RT-
from fed to fasted states may characterize the microbiota
PCR revealed the decline with fasting (up to 28 days) in the
dynamics of the vertebrate intestine among diverse species.
expression of fatty acid synthetase and HSL, and the increase
Metagenomic analysis of microbial sequences from fed and
expression of LPL, all of which were reversed with refeeding
fasted fish, along with qPCR analysis of fish intestinal tissue
(549). The molecular basis of the capacity of elephant seal
suggested that microbial genes related to antibiotic activity
pups to maintain elevated levels of thyroid hormone during
were enriched in response to fasting, and host genes related
postweaning fasting was examined by Martinez et al. (352).
to the immune system were generally upregulated. In contrast
These investigators used RT-PCR to demonstrate a fasting-
to mammalian hibernators (144), fish intestine displayed a
induced increase in mRNA expression of deiodinase type
modest increase in expression of MUC2 mRNA after 3 days
I and type II and thyroid hormone receptor beta-1 within
of fasting followed by a 2.3-fold reduction 6 and 12 days
adipose and muscle tissues, and the upregulation of UPC2
postfasting (590).
within the adipose (352). These techniques revealed seasonal
There is substantial variability in the effects of fasting on
changes in transcript levels of genes that are associated with
hindgut microbial communities, likely due to such factors as
the transitions into and out of hibernation for mammals (14,
host diet and the regularity of feeding patterns in nature, as
59, 64, 155, 168-170, 238, 239, 350, 503, 580, 593-595).
well as the structure of the host’s digestive tract. Investigator-
More recently, the capacity to explore the molecular
driven factors can also contribute, including choice of gut seg-
mechanisms of fasting responses has been enhanced with
ment and microbial community for sampling. At least some
the advent of high-throughput gene expression profiling (e.g.,
of these probably contributed to findings of both unique and
RNAseq) (238, 239, 503). The deep sequencing of the tran-
common effects of fasting on the diversity and composition of
scriptome provides an unparalleled assembly of data on both
hindgut microbiota of animals from five classes of vertebrates
the presence and relative expression of genes. Partnered with
(tilapia, toads, geckos, quail, and mice) (308).

812 Volume 6, April 2016

Comprehensive Physiology Physiology of Fasting

the construction of a species genome, the information mined

Small molecule biochemistry

Carbohydrate metabolism
via bioinformatics is vast. For three fasting model species,

Amino acid metabolism

this sequencing technology has uncovered multiple genes
that are differentially expressed with the onset of fasting. For

Lipid metabolism
the green-striped burrowing frog, 4 months of estivation was
associated with reduced expression of skeletal muscle genes
(A) 6
involved in amino acid transport, and carbohydrate, lipid,
and amino acid metabolism, whereas expression of genes 3
that direct cell death and survival, the maintenance of mus- 0

DNA replication, recombination,

- Log (p-value)
cle integrity, and DNA replication and repair was elevated

Small molecule biochemistry

Cell death and survival

Nucleic acid metabolism
(Fig. 30A) (446). For this frog, gene programs appear to –3
function during estivation to suppress metabolism and pre- –6
serve muscle function.

and repair
–9
Fasting and feeding induced the differential expression
of thousands of genes in the organs of the Burmese python –12
(13, 84, 490). For the heart, liver, small intestine, and kid- –15
ney, fasting is accompanied by elevated expression of tran-
scriptional (DDX21), developmental (CCT5), translational
(EIF4B and Rmb4), and signaling (NCOA4) genes (Fig. 30B).
Feeding is rapidly followed by the downregulation of those (B) 3
genes and the upregulation of metabolic (PDK4 and Slc35b4) 2
and developmental (GPR180) genes among these four organs 1
GPR180 PDK4
Log2 fold change

(Fig. 30B). Underlying the postprandial upregulation of the 0

DDX21 Rmb4
python’s small intestine is the dramatic increase in the expres- –1
sion of genes involved in microvillus lengthening, cytoskele- –2
Heart
tal remodeling, intracellular trafficking, substrate metabolism, –3
Kidney
nutrient transport, and hydrolase activity (13, 490). –4 Liver
For the heart, skeletal muscle, and adipose tissue of –5 Small intestine
13-lined ground squirrels, RNAseq revealed the differential
–6
expression of genes throughout the annual hibernation cycle
(239). Highlights of that study include peaks during win- (C) 4
ter torpor and interbout arousal in the expression of heart 3
NAC1 (sodium/calcium exchanger 1) and PDK4 (pyruvate
dehydrogenase kinase), of skeletal muscle NDRG2 (n-Myc 2
Fold change

downstream regulated gene 2) and PDK4, and of adipose

D
RS
NA
1

O
KC
GL

AC
PCKGC (phosphoenolpyruvate carboxykinase) and PDK4
0
(Fig. 30C). Spring active animals exhibited expression peaks PDK4
1

2
AC

G
XA

in heart NU1M (NADH-ubiquinone oxidoreductase chain 1) –1

R
R
N

AN

D
PA

and CYB (cytochrome b) and in muscle SARCO (sarcolipin) Heart

and GLNA (glutamine synthetase). In August and October,
squirrels experienced peaks in adipose ACOD (acyl Co-A
desaturase) and LEP (leptin).
These technological advances will undoubtedly lead to
an era of studies tracking differential gene expression with
the onset, continuation, and termination of fasting. However,
the confirmation of a causative link between changes in
gene expression and changes in phenotype requires further
analysis beyond simple correlations between the two. It is
important to consider that rather than transcripts, it is proteins
that are responsible for the phenotypic changes that govern
fasting and feeding responses. Given that lack of correlations
between transcript and protein abundances are not uncom-
mon (235, 281), an accurate construction of genotype to
phenotype scenarios requires parallel studies in proteomics
and measures of protein functionality (220). The recent
advances in proteomics (graduation from two-dimensional
–2 Muscle
–3 White adipose
Figure 30 (A) Representation of the up- and downregulation of cellu-
lar function by the differential expression of genes within the gastrocne-
mius muscle of green-striped burrowing frogs (Cyclorana alboguttata)
following 4 months of aestivation. Plots represent the −log of the P value
stemming from Ingenuity Pathway Analysis. (B) Up and downregulation
of genes following a 1 month fast (compared to 1-day fed) for the heart,
kidneys, liver, and small intestine of the Burmese python (Python molu-
rus). Genes include those involved in transcription (DDX21), translation
(Rmb4), development (GPR180), and metabolism (PDK4). Plots illustrate
log2 fold change in expression. (C) Factorial changes in mRNA abun-
dance of genes of the heart, muscle, and white adipose between sum-
mer (August) active and hibernating torpor 13-lined ground squirrels
(Ictidomys tridecemlineatus). Figures drawn, with permission, from data
presented in (84, 239, 446).

Volume 6, April 2016 813

Physiology of Fasting
gel electrophoresis to “shotgun” approaches) can now
provide an escalating characterization of changes in protein
abundance, as exemplified by studies from hibernation
biology (156, 219, 220, 262-264, 470, 507). Coupled with
metabolomics, lipidomics, and bioinformatics, such an
integrative-omics approach will enable researchers to
construct networks that illustrate the dynamic interactions
among integrated physiological systems (30). These net-
works, although challenging to construct due to their layered
complexity, will prove invaluable in comprehending the regu-
latory pathways that underlie the phenotypic transitions from
fed to fasted to refed states and the stabilization of homeosta-
sis during long-term fasting. As new technologies emerge
and as the wealth of genomic, transcriptomic, protein, and
metabolite data increasingly expands, tremendous strides will
be made in understanding and modeling, via a systems biol-
ogy approach, the collective cascade of linked processes that
define an organism’s capacity to initiate and survive fasting
(30,108). The evolution of these networks, driven by indepen-
dent selective regimes that entail long episodes of fasting, will
undoubtedly be dynamic among fasting biologies. Further
exploration and investigation will reveal whether networks
were co-opted and/or have uniquely risen in the evolution of
fasting physiology.
Perspectives
Dictated by predictable environmental change (e.g., hiber-
nation, estivation, and migration), reproductive needs (e.g.,
breeding and care of young) or an animal’s foraging strategy
(e.g., infrequent feeding), extended periods of fasting are
programmed events in the lives of many animals. For fishes,
amphibians, reptiles, birds, and mammals, such extended fasts
elicit a shared suite of phenotypic responses that reduce daily
energy expenditure, switch fuel use to high-energy fat, and
conserve tissues needed during the fast and immediately after.
However, some animals have unique responses to fasting that
presumably reflect strong selective pressures that enhance
survival. In this review, we highlighted both shared and unique
responses to prolonged fasting, emphasizing that such natural
fasts are maintained within the homeostatic boundaries of the
animals. Once that boundary is breached, homeostasis is lost,
and fasting transitions to starvation. Our message is that the
study of fasting biology is not only integrative, but also very
comparative. Studies in this field tend to focus on individual
species and include approaches of horizontal integration that
tie together an animal’s ecology, behavior, anatomy, and
physiology, as well as vertical integration in which physiolog-
ical responses are examined through all levels of organismal
design (whole animal to the molecular). A comparative
approach that targets cellular responses and the coordinated
changes in protein and gene expression would elucidate
whether the mechanisms underlying a common phenotypic
responses (e.g., intestinal atrophy) are shared or unique
among a diversity of taxa and fasting biologies such as mam-
malian hibernation, bird migration, snake infrequent feeding,
814
Comprehensive Physiology
and amphibian estivation. Such research would be transfor-
mative in revealing the ultimate and proximate mechanisms
of fasting phenotypes. It would also be translational for its
insights into the potential for the human body to “turn down
the dial” while preserving tissue and whole body homeostasis,
benefiting certain trauma states and the metabolic flexibility
needed for extended space travel.
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