Starvation: Metabolic
Changes
Malcolm Watford, Rutgers University, New Brunswick, New Jersey, USA
Based in part on the previous version of this eLS article ‘Starvation:
Metabolic Changes’ (2005) by John T Brosnan and Malcom Watford.
Animals, including humans, invoke a comprehen-
sive programme of hormonal and metabolic adap-
tations that enable them to withstand prolonged
periods of starvation. The brain is only capable of
using glucose or ketone bodies as respiratory fuel.
During prolonged starvation, the primary source of
glucose is gluconeogenesis from amino acids aris-
ing from muscle proteolysis. To spare glucose use
(and thus spare muscle protein) most tissues of the
body utilise fat-derived fuels (fatty acid and ketone
bodies). As starvation progresses ketone bodies
also become the major fuel of the brain, again
reducing the need for glucose. High concentrations
of ketone bodies result in significant ketonuria
with ketones excreted as ammonium salts. The
ammonia is derived from the catabolism of glu-
tamine in the kidney with the carbon skeleton
being recovered as glucose. This well-orchestrated
pattern of metabolism allows a consistent fuel sup-
ply to the brain and other tissues during prolonged
starvation.
Fuel Requirements of Different
Tissues
It is important to view starvation as a common event in the lives
of humans and other animals. We are familiar with predatory
animals, such as felids, that kill infrequently, gorge themselves
with food and go without eating for a week or more. Perhaps the
most spectacular example of starvation in the animal kingdom
is provided by the king penguin chick. At the beginning of the
sub-Antarctic winter, the parents leave the chicks to return only
in the spring. The chicks, in colonies of 10 000–100 000, do not
eLS subject area: Biochemistry
How to cite:
Watford, Malcolm (April 2015) Starvation: Metabolic Changes.
In: eLS. John Wiley & Sons, Ltd: Chichester.
DOI: 10.1002/9780470015902.a0000642.pub2
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
Introductory article
Article Contents
• Fuel Requirements of Different Tissues
• The Five Phases of Glucose Homeostasis
• Protein and Amino Acid Metabolism during
Starvation
• Hormonal and Adaptive Control Mechanisms
during Starvation
• Summary
Online posting date: 15th April 2015
feed during this time and their body mass can decrease from about
10–12 kg to 3–4 kg. Survival depends on the timely return of the
parents, who feed them (Cheryl and LeMaho, 1985). Of course,
starvation has also been all too common in human populations.
We are all the descendants of people who have survived famine
and, therefore, we have inherited a pattern of metabolic regulation
that enables us to do so.
By definition, starvation entails no food intake. The starving
individual must, therefore, nourish the different body tis-
sues using stored energy resources. An inventory of the
metabolic fuels available in the standard 70-kg human male
reveals 140 000 kcal fat (15–16 kg) (largely in adipose tissue),
25 000 kcal protein (6 kg) (largely in muscles) and 1000 kcal
glycogen (250 g) (largely in skeletal muscle and liver). The
quantity of fuel (glucose) in the circulation is trivial – about
100 kcal (Cahill, 1970). See also: Energy Balance, Obesity
and Type 2 Diabetes. The conclusion is obvious: the only fuels
present in sufficient quantities for starvation are fat and protein.
Our proteins, however, are not storage proteins. Each plays a
functional role in the body, and, therefore, protein breakdown
during starvation must be limited. It is thus clear that fat must
provide the great bulk of calories during starvation. This has been
known since 1915 when Benedict studied a ‘Mr L’ who fasted for
30 days. Measurement of his urinary nitrogen excretion showed
that protein catabolism provided about 15% of calories. Indirect
calorimetry (measurement of oxygen consumption and carbon
dioxide production) revealed that the rest of Mr L’s energy (about
85%) was provided by fat oxidation (Benedict, 1915).
It is important to understand the fuel requirements of the differ-
ent tissues as these shape the pattern of fuel metabolism during
starvation. The brain is an obligatory glucose user; in the fed
state the brain obtains essentially all of its adenosine triphosphate
(ATP) from glucose oxidation. During prolonged starvation, and
in neonates, the brain also uses ketones, but never to the total
exclusion of glucose. As the brain can obtain sufficient glucose
only when the circulating glucose levels are above 3 mmol L−1 ,
a prime concern throughout starvation is maintaining glucose
above this level. Mammalian red blood cells and some other tis-
sues contain no mitochondria and subsequently have no oxidative
production of ATP; all their ATP is produced by the anaero-
bic conversion of glucose to lactate (glycolysis). The liver is the
great metabolic factory of the body; it can process a variety of
fuels and convert them to forms suitable for utilisation by other
tissues. Thus, the liver is the major organ of gluconeogenesis,
1
 Starvation: Metabolic Changes
producing glucose from amino acids, lactate and glycerol. The
liver is also the sole ketogenic organ, producing acetoacetate and
β-hydroxybutyrate from fatty acids. The liver, however, can oxi-
dise a variety of fuels for its own ATP requirements. Certainly,
in the fed state, it can produce ATP from both amino acid and
carbohydrate metabolism, but during starvation, it relies on the
partial oxidation of fatty acids that also results in ketone body
formation. The fuel metabolism of adipose tissue is rather sim-
ple in that it acts as a calorie bank. In times of excess calories,
triacylglycerol is deposited in adipose tissue; during starvation,
this fat is released via the process of lipolysis, providing fatty
acids and glycerol to the body. Skeletal and cardiac muscle dis-
play considerable plasticity in their fuel requirements. They can
oxidise glucose, fatty acids, ketones, branched chain amino acids
and even lactate, and the ability to change from one fuel to another
is a major theme in the pattern of fuel utilisation during starvation.
See also: Energy Balance, Obesity and Type 2 Diabetes
The principal function of extracellular fuel homeostasis dur-
ing starvation is intracellular ATP homeostasis: the provision of
all tissues of the body with the appropriate mix of fuels so that
they can carry out their physiological functions. It is apparent,
however, that, given our trivial stores of carbohydrate, the pro-
vision of glucose to the glucose-requiring tissues, in particular
to the brain, is the greatest challenge and this shapes the pattern
of fuel metabolism during starvation. Much of our appreciation
of fuel metabolism during starvation comes from the studies of
obese individuals by Cahill and his associates in the 1960s and
1970s (Cahill, 1970, 2006; Felig, 1973; Felig et al., 1969; Marliss
et al., 1971; Owen, 1989; Owen et al., 1969, 1967; Owen and
Reichard, 1971; Sapir and Owen, 1975; Ruderman et al., 1976).
They enunciated two metabolic rules that govern the pattern of
fuel metabolism during starvation: (1) reasonable blood glucose
levels must be maintained for the brain and (2) whenever a tissue
can use either fat or carbohydrate, fat must be preferred [i.e. the
sparing effect of fat on glucose utilisation (Randle et al., 1963)].
40
I II
Glucose utilisation (g h−1)
30
20
10
0 4
Figure 1 Origin of blood glucose and rates of whole body glucose utilisation during the five phases of glucose homeostasis.
2 eLS © 2015, John Wiley & Sons, Ltd. www.els.net
The Five Phases of Glucose
Homeostasis
Despite its small size (approximately 1.5% of bodyweight), the
brain utilises some 20% of our daily calorie expenditure. In the
fed state, this amounts to about 125 g glucose per day. Because
of the importance of glucose homeostasis to the provision of
glucose to the brain, Cahill and coworkers (Ruderman et al.,
1976) analysed fuel metabolism during the progression through
starvation in this context and identified five phases of glucose
homeostasis (Figure 1).
Phase I: absorption
In the fed absorptive phase, blood glucose concentration rises
promptly after consumption of a carbohydrate-containing meal.
This signals to the β cells of the pancreas to release insulin, which
facilitates glucose utilisation and storage by insulin-sensitive
tissues and, at the same time, inhibits adipose tissue lipolysis
resulting in a lowering of circulating free fatty acids. During
this phase, glucose is the body’s predominant fuel and is being
removed from the circulation at a rate of about 40 g h−1 , with
much being stored as glycogen (Figure 1).
Phase II: postabsorption
After dietary glucose has been absorbed, the body depends on
endogenous glucose, either from stores or produced de novo.
This postabsorptive phase runs from about 4 to 16 h after the
meal. A small decrease (from 5 to 3.5 mmol L−1 ) in blood glucose
concentration (Figure 2) translates into a relatively large decrease
in insulin level and an increase in glucagon level. This hormonal
milieu stimulates hepatic glycogenolysis, which provides blood
glucose. The brain continues to use glucose (at about 5 g h−1 ),
and it remains a significant fuel for other tissues, except the
liver. Glucose utilisation in muscle and adipose tissue, however,
III IV V
Diet
Glycogen Gluconeogenesis
8 12 16 20 24 28 2 6 16 24 32 40
Hours Days

8 Total ketone bodies
mmol L−1
4
2 Free fatty acids
0
0 10
Days
Figure 2 Plasma fuel concentrations during prolonged starvation.
is decreased because the fall in insulin concentration decreases
glucose transport into these cells, and, in addition, decreased
inhibition of adipose tissue lipolysis by insulin makes fatty acids
available to the muscle (Figure 2). Total body glucose utilisation
has fallen to about 10 g h−1 (Figure 1).
Phase III: early starvation
After about 16 h of fasting, liver glycogen stores are almost
exhausted and the phase of early starvation continues for per-
haps a further 24 h. Blood glucose levels, of about 3.5 mmol L−1
(Figure 2), are almost entirely sustained by hepatic gluconeoge-
nesis. The substrates for gluconeogenesis are lactate, amino acids
and glycerol. Much of the lactate (some 40 g per day) is produced
by erythrocytes and other glycolytic tissues. Gluconeogenesis
from lactate and most alanine simply recycles ‘old’ glucose (Cori
cycle and glucose–alanine cycle), whereas glycerol and the other
amino acids provide the ‘new’ glucose. The brain continues to
oxidise glucose, but glucose utilisation by other tissues is greatly
attenuated and those tissues that can will use fatty acids as the
major respiratory fuel. Glucose utilisation has fallen to 5–10 g h−1
(Figure 1).
Phase IV: intermediate starvation
Intermediate starvation may be thought of as beginning once
liver glycogen is completely exhausted, some 30–48 h into a
fast. Blood glucose is now provided entirely by gluconeogenesis,
mainly in the liver, although renal gluconeogenesis begins to
make a contribution. Glycerol, derived from lipolysis, provides
about 18 g of new glucose per day, and this is constant throughout
starvation. However, amino acids are substrates for the great
bulk of the new glucose produced. At the start of this phase of
starvation, the brain is oxidising about 120 g glucose per day,
and as about 1.6 g of amino acids are required to produce 1 g of
glucose, some 160 g of amino acids (equivalent to about 800 g of
muscle tissue) must be provided. This rate of proteolysis cannot
be sustained for very long. Therefore, even glucose utilisation by
the brain decreases, by almost 50%, during this phase. Adipose
tissue lipolysis provides fatty acids to the liver, which converts
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
Starvation: Metabolic Changes
Glucose
20 30 40
much of them to ketone bodies (Figure 2), some of which are
used by the brain. Fatty acids and ketone bodies are also used
by such tissues as skeletal and cardiac muscle and the kidneys.
The use of these fat-derived fuels spares glucose utilisation and
thus the need to degrade excessive amounts of body protein. Total
body glucose utilisation is now about 5 g h−1 (Figure 1).
Phase V: late starvation
Late starvation may be thought of as beginning at about 24
days although, of course, there is a gradual continuum between
phases IV and V. Late starvation is characterised by a continuous
decrease in glucose oxidation as the levels of plasma ketones
continue to increase (Figure 2) and they become the dominant
fuel for the brain. Brain glucose utilisation decreases to about
30–40 g per day and there is evidence that it is not entirely
oxidised to carbon dioxide, but that, perhaps as much as half
of the glucose is released as lactate. Fatty acids and ketone
bodies continue to be used by the other tissues, but fatty acid
oxidation becomes proportionally more important in muscle,
which spares ketone bodies for the brain. The high levels of
ketone bodies result in a ketonuria of some 10 g daily. As a
consequence, renal gluconeogenesis (see the following section)
becomes progressively more important and now provides about
50% of the body’s glucose, although it should be recognised
that the rate of hepatic gluconeogenesis is greatly decreased
when compared to earlier stages. Utilisation of glucose has now
decreased to 1–2 g h−1 , half for glycolysis to lactate and half for
oxidation to carbon dioxide. Figure 3 outlines interorgan fuel
metabolism during late starvation. Most of this work was carried
out with obese individuals undergoing total starvation for up to
40 days; more recent work has shown that the general pattern
is true in lean subjects, but there are subtle differences in the
oxidation of proteins and ketone bodies in peripheral tissues
(Elia et al., 1999). See also: Glycolytic Pathway; Glycolysis
Regulation; Glycogen, Starch and Sucrose Synthesis; Fatty
Acid Oxidation; Ketone Bodies; Gluconeogenesis
3
 Starvation: Metabolic Changes

Brain Kidney
CO2 CO2 Glucose

Ketones Lactate Glucose Glutamine Ammonia

(urine)

RBC
Ketones Lactate Glucose Glutamine

Ketones Lactate Glucose Alanine Alanine

Liver FFA Glycerol

Skeletal
muscle
FFA FFA Glutamine Alanine

Glycerol
CO2 Proteins
Adipose
tissue FFA Glycerol

Triacyl glycerols

Figure 3 Interorgan fuel metabolism during prolonged starvation.

Protein and Amino Acid
Metabolism during Starvation
Amino acids are the major substrates for gluconeogenesis to
provide new glucose for the brain. As our body’s proteins are
functional proteins (structural, catalytic, transport and regula-
tory), we cannot catabolise them with impunity. Indeed, the loss
of 30–50% of body protein is incompatible with survival; thus,
proteolysis must be finely controlled. Starvation results in a large
increase in the number of lysosomes in liver, and in the early
phases of starvation, hepatic proteolysis provides amino acids
for gluconeogenesis. Later during starvation, proteolysis predom-
inantly involves muscle protein with relatively minor contribu-
tions from the skin and gut. There is some evidence of increased
lysosomal activity in muscle during starvation, but the bulk of
muscle protein breakdown occurs via the ubiquitin–proteasome
system, and both myofribrillar and noncontractile proteins are
degraded. It is important, however, not to attribute the negative
balance of muscle exclusively to altered proteolysis. Protein syn-
thesis is markedly decreased during starvation and it is clear
that it is the balance between protein synthesis and proteolysis
that is important. The reduction in the circulating insulin level,
which decreases muscle protein synthesis, and the action of glu-
cocorticoids, which increase proteolysis, are the major players in
bringing about net protein degradation in muscle.
The pattern of amino acids released by muscle is also of impor-
tance as it does not reflect the amino acid composition of the
degraded muscle. Rather, alanine and glutamine, which together
with glutamate comprise some 11–15% of muscle, account for
more than 50% of the amino acids released (Felig, 1973; Felig
et al., 1969; Marliss et al., 1971). As muscle does not contain a
specific alanine- and glutamine-rich protein, it is clear that there
is a substantial amino acid metabolism within muscle cells that
transform much of the proteolytically produced amino acids to
alanine and glutamine. It is apparent that the carbon skeleton
of alanine (pyruvate) is largely derived from the small quantity
of glucose that is metabolised by muscle during starvation. The
amino group of alanine is provided by transamination, primarily
from the branched-chain amino acids. The branched-chain amino
acids are released from muscle in relatively small amounts com-
pared with their occurrence (about 25%) in muscle protein; in
fact, their keto acids are extensively catabolised within human
muscle. The released alanine is taken up by the liver, where the
carbon skeleton is converted to glucose and the amino group
converted to urea. This glucose–alanine cycle does not result in
the production of ‘new glucose’. Rather, it serves as a means of
transferring the amino groups of the branched-chain amino acids
to the liver in an innocuous way, without increasing the blood
concentration of the neurotoxin, ammonia. Glutamine production
within muscle involves the enzyme glutamine synthetase, which
uses the energy of ATP hydrolysis to drive glutamine synthesis

4 eLS © 2015, John Wiley & Sons, Ltd. www.els.net


from glutamate and ammonia. Amino acids, such as glutamate,
aspartate, asparagine, valine and isoleucine, are thought to pro-
vide much of the carbon skeleton for glutamine synthesis.
The metabolic fate of the amino acids released by muscle in
starvation is instructive. By and large, the liver removes most
of these for gluconeogenesis (Jungas et al., 1992). Alanine is
regarded as the major hepatic gluconeogenic amino acid. Glu-
tamine plays a more varied role. It is used for hepatic gluconeo-
genesis and it is also the primary respiratory fuel for cells of the
immune system and for the mucosa of the small intestine. In par-
ticular, the partial oxidation of glutamine in the intestine leads to
the production of alanine, which is released to the portal vein and
taken up by the liver, and so the gluconeogenic potential of the
glutamine is conserved (Watford, 1994). During the intermediate
and prolonged starvation phases, however, much of the glutamine
released by muscle is utilised by the kidney for acid–base balance.
The ketone bodies, acetoacetic acid and β-hydroxybutyric acid,
are completely dissociated at physiological pH. As their plasma
concentration increases some 50–100-fold, to 8–10 mmol L−1
(Figure 2), the addition of these acids to the plasma results in a
metabolic acidosis with depletion of bicarbonate. An appreciable
fraction of these ketones escapes renal reabsorption [a ketonuria
of some 100 mEq (10 g) per day], and they are lost in the urine as
their ammonium salts (Owen et al., 1969; Sapir and Owen, 1975).
The urinary ammonia is produced from plasma glutamine, which
is extracted by the kidneys in increasing amounts during starva-
tion. Ammoniagenesis also regenerates bicarbonate to the body,
and the remaining carbon skeleton of glutamine is converted
to glucose by the kidney. Thus, renal gluconeogenesis becomes
more significant as starvation progresses until it produces about
the same quantity of glucose as is produced by the liver at this
24
16
Urea
Nitrogen (g 24 h−1)
12
4 Other nitrogenous compounds
Ammonia
0
1 7
Length of fasting (days)
Figure 4 Daily urinary nitrogen excretion in a male subject who fasted for 38 days.
eLS © 2015, John Wiley & Sons, Ltd. www.els.net
Starvation: Metabolic Changes
time. Figure 4 shows the pattern of urinary nitrogen excretion
during 38 days of starvation. The rate of urinary nitrogen loss (and
hence of protein catabolism) falls progressively, reaching levels
of about 4 g per day, which corresponds to a protein catabolism
of about 25 g per day. It is also evident that the ratio of urinary
ammonia to urea increases until ammonia becomes the major
nitrogenous end product (Owen et al., 1969). This is a direct
indication of the quantitative importance of the kidney, compared
with the liver, in metabolising muscle-derived amino acids dur-
ing prolonged starvation. Indeed, it may be asked whether, in
this situation, acid–base considerations are driving muscle pro-
teolysis, rather than (or in addition to) a need for glucose pro-
duction. Such a question was addressed in experiments in which
prolonged-starved patients were provided with sodium bicarbon-
ate in amounts sufficient to correct the metabolic acidosis. Total
urinary nitrogen excretion decreased by one-third, which indi-
cates that at least this proportion of net protein catabolism is
required by the renal utilisation of glutamine for acid–base home-
ostasis and not the need for glucose production (Fery and Balasse,
1980; Hannaford et al., 1982). See also: Gluconeogenesis; Urea
Cycle; Ketone Bodies
Hormonal and Adaptive Control
Mechanisms during Starvation
Calorie requirements decrease during starvation. It may, of
course, be expected that physical activity will usually decrease
and, obviously, there will be no periods of energy expenditure
associated with the thermic effects of food intake. In addition,
14 21 28 35
5
 Starvation: Metabolic Changes
resting metabolic requirements also fall, in part, due to decreased
circulating levels of triiodothyronine.
As fat-derived fuels become the dominant energy source during
starvation, it is important to understand how they are mobilised
and how they replace carbohydrate. A profound alteration in adi-
pose tissue metabolism occurs as we proceed from the absorp-
tive phase to starvation. Increased insulin levels during the
absorptive phase stimulate glucose uptake via the glucose trans-
porter 4 (GLUT4), and fatty acid release and uptake from very
low-density lipoprotein and chylomicra via the action of lipopro-
tein lipase. This results in high rates of triacylglycerol synthe-
sis and storage in the adipocyte. During starvation, the fall in
insulin levels converts the adipocyte from an organ of fat depo-
sition to one of fat mobilisation. Insulin inhibits lipolysis (at
least, in part, by decreasing cAMP concentrations), and it is
clear that release of this inhibition as insulin levels fall, from
the post-absorptive phase onwards, plays a major role in stim-
ulating lipolysis. Adipose tissue lipolysis involves three lipases:
adipocyte triglyceride lipase (ATGL), hormone-sensitive lipase
(HSL) and monoglyceride lipase (MGL). ATGL is specific for
triglyceride and is responsible for the initial hydrolysis and is
probably regulated by AMP-activated protein kinase. In addition,
catecholamine-induced high levels of cAMP stimulates protein
kinase A that results in the phosphorylation of perilipin, a protein
that surrounds the lipid droplet, protecting it from degradation
by ATGL and HSL. Protein kinase A also phosphorylates HSL
that then moves to the lipid droplet with a resultant increase in
lipolysis (Lass et al., 2011; Zechner et al., 2012). Stimulation
of lipolysis, which releases fatty acids and glycerol from tria-
cylglycerol, may be viewed as the cardinal metabolic event in
the response to starvation as it makes depot fat available to other
tissues. The increased flux of fatty acids to the liver results in
increased ketone body production. This is brought about by both
hormonal and nonhormonal mechanisms. The altered hormonal
milieu increases hepatic β oxidation in two ways: the decreased
insulin level brings about a decrease in malonyl coenzyme A
(CoA) levels and hence a relief from the inhibitory effect of this
compound on carnitine-palmitoyltransferase I (Saggerson, 2008).
In addition, the increased glucagon concentration brings about
an increase in hepatic carnitine levels, although the mechanism
for this effect is unclear. The combination of these two effects,
together with the increase in plasma fatty acid concentrations,
results in increased hepatic β oxidation, which produces large
quantities of acetyl-CoA. What is the fate of this acetyl-CoA? An
obvious fate is oxidation, via Krebs cycle and oxidative phospho-
rylation, to produce large amounts of ATP. The liver, however, can
produce only as much ATP as it can use, and very high rates of
acetyl-CoA production need another outlet. This outlet is the pro-
duction of ketone bodies (Flatt, 1972). Thus, hepatic ketogenesis
can be viewed as an overflow pathway for the disposal of large
quantities of acetyl-CoA produced as a result of rates of β oxida-
tion in excess of those necessary to provide the liver with ATP.
The increased circulating concentration of ketone bodies as star-
vation proceeds is an important factor in their utilisation by the
brain (Figures 1 and 2). Studies with experimental animals sug-
gest that another factor may be an increase in the activity of the
blood–brain barrier transporter that imports these ketone bodies
into the brain.
6 eLS © 2015, John Wiley & Sons, Ltd. www.els.net
Finally, it is important to consider how fatty acids and ketone
bodies replace glucose as the principal fuel for skeletal and
cardiac muscle. The fall in insulin levels both decreases muscle
glucose uptake (by decreased recruitment of GLUT4 to the
plasma membrane) and provides increased quantities of fatty
acids as a result of increased lipolysis. In addition, there are
at least two additional key regulatory events. One key event
resulting in increased fatty acid oxidation is the relief of inhi-
bition of carnitine-palmitoyltransferase I within muscle cells.
This enzyme, which regulates the entry of fatty acyl groups
into mitochondria, is inhibited in the fed state by malonyl-CoA.
This malonyl-CoA is produced by a particular isoform of
acetyl-CoA carboxylase (ACC-2). Insulin activates ACC-2 via
a signalling cascade that results in dephosphorylation of the
enzyme (Brownsey et al., 2006; Saggerson, 2008). In starvation,
however, the low-insulin environment results in phosphorylation
and inhibition of the enzyme, together with concomitant activa-
tion of malonyl CoA decarboxylase, with a consequent decrease
in malonyl-CoA levels, increased carnitine-palmitoyltransferase
I activity and increased fatty acid oxidation (Ruderman et al.,
1999; Saggerson, 2008). See also: Insulin and Glucagon; Fatty
Acid Oxidation; Ketone Bodies. The other key regulation
occurs at the pyruvate dehydrogenase complex (PDHC). This
enzyme complex, which is activated by insulin, is inhibited (by
phosphorylation) in the absence of insulin. The inhibition of this
enzyme, in starvation, occurs in a wide variety of tissues and is
regulated by tissue-specific pyruvate dehydrogenase kinase and
phosphatase isozymes. As PDHC is irreversible and its product,
acetyl-CoA, cannot be converted to glucose, any flux through
this enzyme in any tissue represents the loss of gluconeogenic
precursors. It is essential that these precursors, lactate produced
by glycolytic tissues and muscle-derived amino acids that are
converted to pyruvate (alanine, cysteine, glycine, serine, threo-
nine and tryptophan), be used for gluconeogenesis rather than
for oxidation. The tissue-specific inhibition of PDHC, during
starvation, ensures that this occurs (Harris et al., 2002; Joeung
and Harris, 2010). See also: Pyruvate Dehydrogenase Complex
Summary
Much of our scientific knowledge about starvation comes from
carefully controlled studies, with obese or normal-weight volun-
teers, in clinical settings. These individuals were supplied with
adequate micronutrients. There are also, sadly, too many reports
of starvation as a result of famine and war. These individuals also
face micronutrient deficiencies, increased exposure to infections
(in particular, fungal, bacterial and parasitic diseases) and to hos-
tile physical environments. The basic features of the metabolic
response to starvation in these situations appear to be the same
as those revealed by the clinical studies. The cardinal features of
this response are (1) the mobilisation of depot fats and their utili-
sation as fuels, to the exclusion of glucose, by most of the tissues
of the body and (2) the production of new glucose from gluco-
neogenic precursors (principally muscle-derived amino acids and
adipose tissue-derived glycerol). Provision of fuels (glucose and
ketone bodies) to the brain is crucial, and it should be recognised
that this is a greater challenge in humans than in other animals,

because of the relatively large size of our brains. Similarly, the
large brain to bodyweight ratio, together with limited fuel stores,
means that children cannot undergo prolonged starvation. Much
of the metabolic response to starvation is orchestrated by hor-
monal changes, with decreased insulin and increased glucagon
levels being particularly important. Conservation of body protein
is crucial. Indeed, ultimately, death from starvation can often be
attributed to protein depletion. In situations where starvation is
complicated by infection, it may be that the increased proteolysis
associated with the metabolic response to infection will exac-
erbate the situation and reduce the length of time for which an
individual can starve successfully.
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Further Reading
Benedict FG (1915) A Study of Prolonged Fasting. Washington:
Carnegie Institute.
Cahill GF Jr, (1970) Starvation in man. New England Journal of
Medicine 282: 668–675.
Cahill GF Jr, (2006) Fuel metabolism in starvation. Annual Review
of Nutrition 26: 1–22.
Keys A, Brozek J, Henschel A, Mickelsen O and Taylor HL (1950)
The Biology of Human Starvation. Minneapolis: University of
Minnesota Press.
Ruderman NB, Aoki TT and Cahill GF Jr, (1976) Gluconeogenesis
and its disorders in man. In: Hanson RW and Mehlman MA,
(eds). Gluconeogenesis: Its Regulation in Mammalian Species, pp.
515–532. New York: John Wiley.
Wahren J and Ekberg K (2007) Splanchnic Regulation of Glucose
Production. Annual Review of Nutrition 27: 329–345.
Winick M (1979) Hunger Disease: Studies by the Jewish Physicians
in the Warsaw Ghetto. New York: John Wiley.
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