Physiology & Behavior 220 (2020) 112873

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Physiology & Behavior

journal homepage: www.elsevier.com/locate/physbeh

Review

Circadian regulation of appetite and time restricted feeding T

a,b,⁎ a c,d a,b
Amanda J. Page , Stewart Christie , Erin Symonds , Hui Li
a
Vagal Afferent Research Group and Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, University of Adelaide,
Adelaide, SA 5000, Australia
b
Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA 5000, Australia
c
Bowel Health Service, Flinders Medical Centre, Bedford Park, SA 5042, Australia
d
Flinders Centre for Innovation in Cancer, Flinders University, Bedford Park, SA 5042, Australia

A R T I C LE I N FO A B S T R A C T

Keywords: The circadian system plays an important role in the temporal regulation of metabolic processes as well as food
Circadian intake to ensure energy efficiency. The ‘master’ clock is located within the superchiasmatic nucleus and receives
Food intake input from the retina so that it can be entrained by the light:dark cycle. In turn, the master clock entrains other
Time-restricted feeding clocks in the central nervous system, including areas involved in energy homeostasis such as the arcuate nucleus,
Food-entrainable oscillator
and the periphery (e.g. adipose tissue and the gastrointestinal tract). This master clock is reinforced by other
zeitgebers such as the timing of food intake and activity. If these zeitgebers desynchronise, such as occurs in high
fat diet-induced obesity or shift work conditions, it can lead to a misalignment of circadian clocks, disruption of
metabolic processes and the development of metabolic disorders. The timing of food intake is a strong zeitgeber,
particularly in the gastrointestinal tract, and therefore time restricted feeding offers potential for the treatment
of diet and shift work induced metabolic disorders. This review will focus on the role of the circadian system in
food intake regulation and the effect of environment factors, such as high fat diet feeding or shift work, on the
temporal regulation of food intake along with the benefits of time restricted feeding.

1. Introduction light:dark cycle. The role of circadian rhythms in the synchronisation of

In animals, the acquisition of energy to maintain life requires the
intake of food. As a consequence, evolution has developed a sophisti-
cated and well-integrated system to finely control energy intake.
Centrally, the hypothalamus plays a key role in food intake regulation.
This area receives peripheral input from the gastrointestinal tract, for
the short-term regulation of meal size and meal frequency, and adipose
tissue, for the long-term regulation of energy homeostasis. The pro-
cesses that regulate energy homeostasis rely on a balance between or-
exigenic and anorexigenic factors. Circadian signals have an important
role in energy homeostasis [1], temporally regulating these opposing
factors and maximising energy efficiency. For example, circadian
rhythms facilitate the temporal occurrence of related physiological
functions, such as food intake and glycogenesis.
‘Circadian’ is from the Latin words Circa and diem which translates
to ‘about a day’ and circadian rhythms occur over about a 24 h period.
Many components of physiology, metabolism and behavior display
circadian rhythms. These rhythms are generated by endogenous clocks
that possess highly conserved timing mechanisms enabling organisms
to participate and adapt to daily environmental fluctuations, such as the
processes such as food intake and metabolism ensure efficiency of en-
ergy homeostasis. However, disruption of these rhythms can lead to
metabolic disorders, such as obesity. Conversely, obesity may disrupt
circadian rhythms perpetuating the problem.
The present review is focused on appetite regulation, the role of the
circadian system in controlling these signals and the potential of time
restricted feeding to reverse the adverse effects of shift work or obesity
on disruption of these circadian satiety signals.
2. Circadian clock system
The circadian clock is complex but basically consists of a central
clock, the ‘master’ clock, located in the suprachiasmatic nucleus (SCN)
of the anterior hypothalamus and peripheral clocks [2]. The master
clock coordinates the majority of daily rhythms. The SCN is composed
of multiple, single cell circadian oscillators, which generate coordinated
circadian signals, if synchronised, to regulate physiological rhythms.
The SCN receives input from the retina via the retinohypothalamic tract
which enables entrainment of the SCN oscillators to the 24 h light-dark
cycle [3].

⁎
Corresponding author at: Vagal Afferent Research Group, Adelaide Medical School, University of Adelaide, Adelaide, SA 5000, Australia.
E-mail address: amanda.page@adelaide.edu.au (A.J. Page).

https://doi.org/10.1016/j.physbeh.2020.112873
Received 9 December 2019; Received in revised form 1 February 2020; Accepted 10 March 2020
Available online 16 March 2020
0031-9384/ © 2020 Elsevier Inc. All rights reserved.
A.J. Page, et al.
The molecular mechanisms, which drive these circadian oscilla-
tions, consists of a series of interlocking molecular loops, involving
rhythmic transcription of specific clock genes and interactions of the
proteins they encode. In very basic terms, clock genes consist of positive
elements, such as Brain and Muscle ARNT-Like 1 (BMAL1), Circadian
Locomotor Output Cycles Kaput (Clock) and neuronal PAS domain
protein 2 (NPAS2). BMAL1 forms a heterodimer with either Clock or
NPAS2, enters the nucleus and stimulates transcription of negative
elements, such as period 1, 2 and 3 (Per 1–3) and cryptochrome 1 and 2
(Cry 1–2) [4-6]. The protein products of these genes heterodimerise,
translocate to the nucleus and inhibit the activity of the BMAL1/Clock
complex. Further, a number of nuclear receptors, such as REV-ERB and
ROR interact with or can be considered core components of the circa-
dian clock [7]. For example, BMAL1/Clock activates REV-ERBα tran-
scription resulting in daily fluctuations in REV-ERBα, which, in turn,
represses the transcription of BMAL1 [8,9]. In contrast, RORα stimu-
lates BMAL1 expression [10]. These nuclear receptors act as a physio-
logical signaling relay enabling the clock rhythms to be influenced by
nutrient signals (e.g. derivatives of fatty acids), hormonal signals (e.g.
cortisol) and cellular redox status and vice versa [11-13]. Similar clock
oscillators have also been found in other central areas and in peripheral
tissues, such as the gastrointestinal tract, liver, muscle and adipose
tissue. The SCN sends signals, via neural connections or circulating
humoral factors, to the peripheral clocks to prevent dampening of the
circadian rhythms in the peripheral tissues [14]. In addition to light,
feeding episodes, signalled by the gastrointestinal tract, and availability
of metabolites, represents another important synchroniser for central
and peripheral clocks [15]. Restriction of food availability to a narrow
window each day (time-restricted feeding) has been demonstrated to
result in a profound reorganisation of behavior and physiology [16,17].
Such restriction of food availability induces a bout of activity, known as
food anticipatory activity, in advance of food availability. These food
anticipatory activities display properties consistent with control by
endogenous circadian clocks rather than a food-driven phenomenon.
For example, if the period of food availability is abruptly delayed the
onset of food anticipatory activity takes multiple days to resynchronise.
Further, if the animal is completely food deprived the onset of the food
anticipatory activity persists for as long as the fasting period can be
maintained [16,17].
3. Food intake regulation
3.1. Central regulation of food intake
There are many brain regions, including the hypothalamus, hind-
brain and corticolimbic system, that play a role in the control of food
intake [18]. In particular, the hypothalamus is composed of many nu-
clei with various functions associated with energy homeostasis [19]. In
relation to food intake the most relevant hypothalamic areas include
the arcuate nucleus (ARC), paraventricular nucleus (PVN), lateral hy-
pothalamic area (LHA), ventral medial nucleus (VMN) and dorsal
medial nucleus (DMN; Fig. 1). The ARC is located in the mediobasal
hypothalamus and contains two distinct opposing populations of nuclei:
those that express pro-opiomelanocortin (POMC) [20] and cocaine and
amphetamine regulated transcript (CART) [21], and those that express
neuropeptide Y (NPY) and agouti-related peptide (AgRP) [22]. The
POMC/CART neurones are considered anorexigenic with their activa-
tion reducing food intake. These neurones can be stimulated by leptin
and insulin and inhibited by ghrelin [23]. POMC is a precursor for
many peptides, including α-melanocyte stimulating hormone (α-MSH)
[24]. α-MSH binds to the melanocortin receptor 3 (MCR3) or the MCR4
to inhibit food intake [25,26]. Conversely, NPY/AgRP neurones are
orexigenic with their activation increasing food intake [27,28]. These
neurones can be stimulated by ghrelin and inhibited by leptin and
peptide tyrosine-tyrosine (PYY) [29]. NPY binds to Y1 receptors [30]
and AgRP acts as an antagonist at MCR3 and MCR4 [31] to prevent α-
2
Physiology & Behavior 220 (2020) 112873
Food Intake
PVN
DMN LHA
BBB
Anorexigens POMC Dorsal
CART VMN
NPY
AgRP
Orexigens ARC
Ventral
Medial Lateral
Oscillatory signalling
Fig. 1. Hypothalamic nuclei involved in appetite regulation. The major hy-
pothalamic nuclei involved in appetite regulation are the arcuate nucleus
(ARC), dorsal medial nucleus (DMN), ventral medial nucleus (VMN), para-
ventricular nucleus (PVN), and lateral hypothalamic area (LHA). Green lines
represent activation, red lines represent inhibition. The ARC contains two op-
posing nuclei expressing either: neuropeptide Y (NPY) and agouti-related
peptide (AgRP) or pro-opiomelanocortin (POMC) and cocaine and ampheta-
mine related transcript (CART). NPY/AgRP neurons from the ARC inhibit the
PVN, DMN, and VMN, and stimulates the LHA to increase food intake. POMC/
AgRP neurons from the ARC inhibit the LHA and stimulate the PVN, DMN, and
VMN to inhibit food intake. The ARC is adjacent to a weak blood brain barrier
(BBB) and is therefore capable of being regulated by blood borne signals such as
orexigens (e.g. ghrelin) and anorexigens (e.g. leptin). The daily feed-fast cycle is
controlled by oscillations in all areas of the hypothalamic nuclei, involved in
food intake, which receives input for the master clock in the suprachiasmatic
nuclei of the hypothalamus.
MSH binding and the subsequent inhibition of food intake.
POMC/CART and NPY/AgRP neurones in the ARC project to other
hypothalamic nuclei including the PVN, LHA, VMN and DMV [23]. The
PVN is linked with satiety [32] and is stimulated by POMC/CART
neurones and inhibited by NPY/AgRP neurones [19]. Conversely, the
LHA is considered orexigenic and contains two populations of neurones
expressing either orexin or melanin concentrating hormone (MCH)
[33,34]. These subsets of neurones are stimulated by NPY/AgRp neu-
rones and inhibited by POMC/CART neurones [19]. The VMN and DMN
also receive projections from the ARC where they are stimulated by
POMC/CART neurones and inhibited by NPY/AgRP neurones [19].
It has been demonstrated that the circadian system orchestrates the
temporal regulation of metabolic processes over a 24 h cycle, giving rise
to diurnal rhythms in energy expenditure [35,36], appetite [37-40] and
insulin sensitivity [41-43]. Anatomical studies have identified connec-
tions between the SCN and several hypothalamic and extra-hypotha-
lamic areas, including the subparaventricular region, PVN, ARC, lateral
geniculate nucleus and raphe nuclei [44-47]. These connections are
important for the coordination of daily physiological rhythms, such as
food intake, energy expenditure, locomotor activity and temperature.
The rhythmic activity of neuroendocrine neurones within the hy-
pothalamus, including gene and protein expression of many of the
neurotransmitters within the hypothalamic region [48-50], is regulated
through these connections [51] and may be required for the circadian
regulation of appetite. For example, it has been shown that the in-
creased food intake at the onset of the dark phase is reduced in mice
lacking NPY [52], suggesting circadian rhythmicity of NPY in the hy-
pothalamus is driving diurnal rhythms in food intake. In addition,
A.J. Page, et al.
expression of the clock gene REV-ERBα in the brain has been shown to
control the circadian organisation of food intake [53]. Circadian
rhythms may also explain the persistent basic eating patterns in hu-
mans, which has been observed in individuals isolated from external
time cues, such as the light-dark cycle [54].
Central reward mechanisms also play an important role in influen-
cing food intake behavior. The reward system exerts distinct actions
through brain systems and neural pathways, such as the corticolimbic
(e.g. amygdala, prefrontal cortex and hippocampus) and mesolimbic
(e.g. nucleus accumbens, striatum and ventral tegmental area (VTA))
systems [19] which represent the ‘liking’ and ‘wanting’ areas respec-
tively [55,56]. Further, the mesolimbic dopamine system is thought to
be the major reward seeking pathway [57]. Rhythmic dopamine release
has been reported in the dorsal striatum [58] and this rhythmicity
drives rhythmicity of Per2 in the rat dorsal striatum but not the SCN
[59].
The metabolic status of an individual is also relayed, in a circadian-
dependent manner, via humoral and neural signals from the peripheral
tissues to the brain regions that control appetite [60]. In the following
sections the input from adipose tissue and the gastrointestinal tract, (i.e.
involved in the long and short-term regulation of energy homeostasis
respectively) will be discussed.
3.2. Adipose tissue
White adipose tissue generally serves as the body's energy store
where it can be utilised when energy intake is low. However, white
adipose tissue also secretes many peptides or adipokines that can reg-
ulate energy balance and metabolism, such as leptin. After secretion
from adipose tissue, leptin enters the circulation and, via a saturable
transport protein [61], can cross the hypothalamic blood brain barrier.
Here it binds to its receptor in the ARC causing inhibition of NPY and
activation of POMC neurones with a resultant reduction in food intake
[62] and increase in energy expenditure [63, 64]. It should be noted,
that leptin can also act on other areas throughout the brain to control
feeding and feeding behavior, including the hindbrain, hippocampus
and limbic brain regions [65]. Leptin is secreted in proportion to adi-
pocyte size and adipose mass [66]. However, it is also secreted in a
circadian manner [67,68]; under the control of the SCN via sympathetic
input to the adipocytes [69]. In humans, plasma leptin levels are high
during the night favouring fasting and nocturnal rest. In contrast,
during the daytime leptin levels are comparatively low permitting the
intake of food during the active period when energy demands are high.
In obese individuals, leptin levels are elevated, however, circulating
diurnal level of leptin are still maintained but with lower amplitude
[70,71]. With central leptin resistance the significance of circulating
diurnal leptin levels in appetite regulation is questionable [72]. This
indirect SCN signaling, via adipose tissue, will reinforce the temporal
regulation of food intake and metabolism centrally.
3.3. Gastrointestinal tract
The gastrointestinal tract plays a vital role in food intake, digestion
and absorption of nutrients. There is substantial evidence that the
gastrointestinal tract contains functional clock genes [73-75] and it also
receives input from the SCN via humoral and neural pathways. Clock
genes are present throughout the gut, including the myenteric plexus
and the epithelial cells, suggesting a role in the generation of daily
rhythms in gastrointestinal functions, such as gastrointestinal motility
(e.g. gastric emptying), gastric secretions, enzymatic activity, and nu-
trient detection and absorption in the small intestine [76,77]. This
circadian rhythmicity provides the gastrointestinal tract the ability to
anticipate a meal and optimally prepare for the transit and absorption
of nutrients. This review will focus on the gut-brain axis and appetite
regulation.
The gut-brain axis plays an important role in the short-term
3
Physiology & Behavior 220 (2020) 112873
regulation of food intake. This axis is comprised of neural vagal afferent
and endocrine signals that coordinate to regulate food intake. There is
evidence that all aspect of this axis displays diurnal rhythms to regulate
the timing of food intake, maximising digestion and nutrient absorption
as well as aligning food intake with energy requirements.
3.3.1. Vagal afferents
Gastrointestinal vagal afferents play an important role in the control
of food intake. Vagal afferents respond to mechanical and chemical
stimuli relaying information to the nucleus tractus solitarius (NTS). It is
generally believed that this information is then passed to the hy-
pothalamus where it is integrated with other signals eventually leading
to feelings of fullness and satiety with subsequent changes in feeding
behavior. However, decerebrate rats, that lack the hindbrain to fore-
brain connections, are also capable of terminating a meal suggesting
that some aspects of food intake control are represented in the caudal
brain areas [78]. Gastric vagal afferents are predominantly mechan-
osensitive [79,80], responding to the arrival and amount of food in the
stomach. Gut hormones such as leptin [81] and ghrelin [82,83] are able
to modulate the sensitivity of these mechanosensitive afferents. In the
small intestine, there is an enteroendocrine response to nutrients, where
specific nutrients interact with a nutrient receptor initiating an in-
tracellular process that culminates in the release of a gut hormone
[84,85], such as cholecystokinin (CCK). These gut hormones can then
either act directly on vagal afferent endings or enter the circulation to
act in an endocrine manner on central sites of appetite regulation.
Further, it has recently been demonstrated that duodenal mechan-
osensitive afferents play a major role in food intake regulation [86].
There is limited information available on the role of the circadian
system in the regulation of vagal afferent function. However, it has been
demonstrated that gastric vagal afferents display diurnal rhythms in
response to mechanical stimuli [87]. These rhythms are lost in high fat
diet-induced obese mice [88] and/or simulated shift work conditions
[89], and associated with a ‘grazing-like’ behavior in food intake
(Fig. 2).
3.3.2. Nutrient sensors
Although there is evidence that intestinal nutrient transporters, such
as sodium-glucose transporter 1 (SGLT1), glucose transporters (GLUT;
GVA signaling
‘Normal’ Diurnal rhythms
condions in GVA signaling
Loss of rhythms
High fat diet
in GVA signaling
Grazing
Loss of rhythms
Shi work in GVA signaling
Grazing
Fig. 2. Schematic of the effect of light:dark cycle and diet on diurnal rhythms in
gastric vagal afferent responses to food related stimuli in mice. Under ‘normal’
conditions the light cycle and food intake patterns are coordinated leading to
diurnal rhythms in gastric vagal afferent signaling. In high fat diet conditions
there is a disrupted ‘grazing-like’ feeding behavior resulting in a loss of diurnal
rhythms in gastric vagal afferent signaling. Similarly, in simulated shift work
conditions diurnal rhythms in food intake are disrupted leading to a loss of
diurnal rhythms in gastric vagal afferent signaling.
A.J. Page, et al. Physiology & Behavior 220 (2020) 112873

A Relative T1R2 mRNA

0.0005 pattern of secretion independent of nutrient stimulation.
0.0004 Leptin is not only expressed in adipose tissue but is also expressed in
expression the stomach [97,98]. Gastric leptin levels oscillate in a circadian
0.0003
manner with leptin levels high at night and low during the day in hu-
0.0002 mans [99]. Leptin modulates gastric vagal afferent mucosal receptor
0.0001 ** Vs
** ** ** mechanosensitivity [81] and, therefore, it is possible that diurnal
0.0000 12Hrs rhythms in gastric leptin levels are driving diurnal rhythms in gastric
0 3 6 9 12 15 18 21
Zeitgeber (Hrs) vagal afferent mucosal receptor mechanosensitivity. Further, the mod-
B ulatory effect of leptin on gastric vagal afferent mucosal receptors
Relative GPR93 mRNA

0.04 displays diurnal rhythms with potentiation of gastric vagal afferent

0.03 mucosal receptors during the light phase; an effect that diminishes
expression

during the dark phase in mice [88].

0.02 Ghrelin is also produced in the stomach [100,101] and is involved
0.01 in stimulating appetite via its central action on neuropeptide Y in the
lateral hypothalamus [102,103] and peripheral action on gastric vagal
0.00
0 3 6 9 12 15 18 21 afferents [82,83]. Ghrelin can also alter clock function in the SCN
Zeitgeber (Hrs) [104,105] and, hence, may be a signal involved in the cross-talk be-
C tween the peripheral and central clock system. Ghrelin oscillates with
Relave CaSR mRNA

0.0003
feeding [106], making this peptide a candidate for food-related en-
expression

0.0002 training signals. In humans, circulating levels of ghrelin are high during
the dark phase and relatively lower during the light phase [72].
0.0001 A number of other gut peptides, including glucagon-like peptide-1
(GLP-1) and PYY [107] and CCK [108] are thought to display circadian
0.0000 rhythms in circulating plasma levels, however, it is difficult to tease out
0 3 6 9 12 15 18 21
the impact of food intake from the circadian cycle on these diurnal
Zeitgeber (Hrs)
rhythms.
D
Relative GPR40 mRNA

0.0020
3.3.4. Microbiota
0.0015
expression

There is mounting evidence to suggest that the gut microbiota in-

0.0010
0.0005
0.0000
0 3 6 9 12 15 18 21
Zeitgeber (Hrs)
Fig. 3. Expression of nutrient receptors in the mouse proximal jejunum over a
24 h period. Expression of the (A) sweet taste component T1R2; (B) protein
hydrosylate receptor (GPR93); (C) amino acid receptor (calcium sensing re-
ceptor (CaSR)) and (D) long chain fatty acid receptor (GPR40 (aka FFAR1))
mRNA in the mouse (N = 6) proximal jejunum relative to GAPDH. **P < 0.01
vs ZT12; one-way ANOVA. Zeitgeber is hours since lights on.
GLUT2 and GLUT5) and the proton-coupled oligopeptide transporter 1
display diurnal rhythmicity [90-94], with peak expression during the
dark phase in rodents, there is little known on the diurnal expression of
nutrient receptors. Unpublished data (Fig. 3) indicate that a component
of the sweet taste receptor T1R2 displays diurnal rhythms in mRNA
expression (Fig. 3A) in the mouse proximal jejunum; an effect not ob-
served in the rat jejunum [95]. This discrepancy may be due to the lack
of sufficient time points, particular the time-point of peak expression, in
the study by Bhutta et al. [95] or simply due to species differences. In
contrast, no rhythmicity in the expression of protein hydrosylate re-
ceptor (GPR93; Fig. 3B), amino acid receptor (calcium sensing receptor;
Fig. 3C) and the long chain fatty acid receptor mRNA (GPR40 (aka
FFAR1); Fig. 3D) were observed in the mouse proximal jejunum. These
differences may be related to their role in specific regions of the gas-
trointestinal tract and the local drivers of these rhythms. For example,
diurnal fluctuations in microbial short chain fatty acid production is
thought to drive diurnal expression of free fatty acid receptor 2 (FFAR2)
and FFAR3 in the colon [96].
3.3.3. Gut hormones
Gut hormones are released from the gastrointestinal tract to co-
ordinate the timing of food intake and the absorption and utilisation of
nutrients in the body. The majority are released in response to nu-
trients, however, some are known to follow a circadian anticipatory
fluences the host's homeostatic processes and modulates the develop-
ment of obesity and type 2 diabetes. Microbial products, such as short
chain fatty acids (SCFAs) and succinate, can alter intestinal gluconeo-
genesis [109,110]. In addition, the microbiota affects circulating sig-
nals, enteric neurons and vagal afferents that carry hunger and satiety
cues to the brain [111]. The gut microbiota also contributes to the
diurnal communication between the gut and the brain participating in
the circadian regulation of food intake. The gut microbiota has been
shown to modulate various host gastrointestinal clocks [112,113]. In
turn, the hosts circadian system, feeding schedules as well as diet
composition have a major effect on the daily fluctuations of the mi-
crobiota in mice and humans [114-116]. Removing the gut microbiota
has been shown to impair clock gene expression in the intestinal epi-
thelial cells, liver and mediobasal hypothalamus [112,114]. The ques-
tion is whether the microbiota is controlling the gut clock or vice versa.
The circadian clock within the intestinal epithelial cells is profoundly
disrupted by depletion of the microbiota [112] and therefore it would
appear that the microbiota is determining the function of the gut clock.
However, the composition of the microbiota undergoes diurnal oscil-
lations in mice and humans [117] and these oscillations are disrupted in
mutant mice with a genetic mutation in the clock system and jet-lag
experiments [96,117,118]. Therefore, the communication appears to be
bi-directional. However, it is difficult to untangle direct communication
between the gut and microbiota and indirect effects due to changes in
feeding behavior.
4. Timing of food intake and time-restricted feeding
The light-dark cycle is not the only regulator of circadian rhythms.
Food is a very potent zeitgeber especially for clocks in the gastro-
intestinal tract. If rodents have access to food only during the light
phase, when they are normally docile, they will adjust to this feeding
schedule within a few days. This includes the display of food antici-
patory activity, such as increased locomotor activity, temperature, di-
gestive enzyme activity and gastrointestinal motility, a few hours be-
fore food becomes available [17,119,120]. In addition, the rhythms in
clock gene expression realign with the new feeding schedule [121-123].

4
A.J. Page, et al.
For example, there are studies that demonstrate that the liver clock can
be entrained by time-restricted feeding independently of the SCN and
the light cycle [124,125]. Under ‘normal’ conditions, animals and hu-
mans have a diurnal rhythm in food intake with the major proportion of
24 h food intake consumed during the natural wake period. These daily
eating-fasting rhythms are aligned with other zeitgebers, such as ac-
tivity and the light-dark cycle, where they can act synergistically to
drive daily rhythms in appetite, anabolism and catabolism. Further, it
has been shown that abandonment of regular eating patterns, due to the
increased demands imposed by contemporary 24 h societies, disrupts
nutritional and metabolic processes leading to profound effects on long-
term health and well-being [126–128]. It should be noted that mis-
alignment can occur for a number of reasons, including shift work,
exposure to prolonged hours of artificial light and erratic eating pat-
terns. It is difficult to separate the outcomes of these perturbations as
one factor often leads to disruption of another factor. For example, shift
workers generally eat at the wrong time of day due to their altered
sleep-wake patterns. Nonetheless, it is clear that anything that causes
misalignment of the peripheral and central clocks will lead to disrup-
tion in food intake patterns along with metabolic misalignment that
ultimately contributes to the development and maintenance of obesity
and its co-morbidities, such as type 2 diabetes mellitus and cardiovas-
cular disease.
In today's industrial society a large proportion (~15–20%) of the
working population are shift workers [129–131] including permanent
night shifts, rotating shifts or irregular schedules. During the night shift,
workers are exposed to prolonged hours of artificial light and increased
activity. There are also changes in feeding patterns with shift workers
tending to schedule their meals around their working hours resulting in
increased food intake during the normal resting phase [132–135].
Further, on days off shift workers revert back to a more social daytime
schedule; imposing a jet-lag paradigm as the central and peripheral
clocks try to adjust to the new schedule. As a consequence, working
shift work is a risk factor for health with shift workers more likely to
become overweight than their day-shift counterparts [136]. It has been
demonstrated that although the amount of food consumed does not
vary between the night shift and the day shift or days off [137] the
pattern of food intake is dramatically changed with participants eating
around the clock, while they are on night shift, with no extended fasting
periods [138]. A study has demonstrated a difference in the energy
expenditure response to the same meal depending on the time the meal
was consumed; with morning diet-induced thermogenesis significantly
higher than afternoon and night diet-induced thermogenesis [139].
Therefore, although the same calories were consumed, the time-de-
pendent differences in thermogenesis may significantly impact on
weight gain in shift workers and highlights the importance of co-
ordinating food intake with metabolic processes. Under a normal 12
h:12 h light:dark cycle ad libitum standard laboratory diet fed mice
display diurnal rhythms in food intake, with 60–80% of food consumed
during the dark phase [87]. These food intake patterns were shown to
be negatively associated with gastric vagal afferent responses to food
related stimuli [87]. In contrast, mice exposed to simulated shift work
conditions (a normal light cycle (lights on at ZT0: Lights off at ZT12) for
3 days followed by a reverse light cycle (lights on at ZT12: lights off at
ZT0) for 4 days, repeated for 8 weeks) displayed a ‘grazing-like’ be-
havior and a dampening in diurnal rhythms in food intake [89]. This
was associated with a loss of diurnal rhythms in gastric vagal afferent
satiety signaling [89]. It is unclear whether the ‘grazing-like’ behavior
is causing the loss in diurnal rhythms in gastric vagal afferent satiety
signals or the other way around and longitudinal studies are required to
address this question.
Artificial light has extended the day period leading to an extension
of the feeding period. The increase in availability of light at night
parallels the increased rates of obesity [126,140]. A study, using a
smart-phone app to monitor food intake and eating patterns, demon-
strated that over half of the participants had feeding episodes spanning
5
Physiology & Behavior 220 (2020) 112873
over 15 h per day [141], reducing the fasting period and disrupting the
circadian alignment of the peripheral and central clocks. Male and fe-
male mice exposed to a dim light at night gained more weight than mice
exposed to a normal light:dark cycle [126,142]. Interestingly, this was
not due to an increase in total daily food intake but rather a change in
eating patterns, with an increase in food intake during the light phase
compared to mice exposed to a normal light cycle [126].
The availability of calorie dense diets can also impact on the cir-
cadian system. For example, rodents fed a high fat diet shift their pat-
tern of food intake so that they display a ‘grazing-like’ behavior, with
increased food intake during the light phase compared to animals fed a
standard laboratory diet [88,143]. These changes in behavioral rhyth-
micity correlate with disrupted clock gene expression in the hypotha-
lamus, peripheral tissue, such as the liver and adipose tissue, as well as
altered cycling hormones, such as leptin, thyroid stimulating hormone
and testosterone in rodents and humans [143–148]. Diurnal rhythms in
peripheral gastric vagal afferent satiety signaling is also lost in high fat
diet-induced obesity [88], however, it is still unclear whether the dis-
ruption in food intake is causing the disruption in the circadian system
or vice versa. Nonetheless, the use of time restricted feeding to reinforce
circadian rhythms and provide temporal regulation of appetite, as well
as anabolism and catabolism, is an attractive option.
4.1. Time-restricted feeding
The concept of time-restricted feeding as a potential intervention for
metabolic disease arose from studies that examined the effect of time
restricted food intake on behavior and clock components in metabolic
organs, such as the liver (see [149]). As stated above animals and hu-
mans have diurnal rhythms in food intake with the majority of food
consumed in the active natural wake period. Due to the reciprocal in-
teraction between metabolism and the circadian clock, these diurnal
rhythms in food intake act synergistically with the molecular circadian
clock to drive daily rhythms in appetite, anabolism and catabolism. A
high fat diet disrupts feed-fasting rhythms in animals, with food intake
spread over a 24 h period. These erratic eating patterns can contribute
to or perpetuate the disruption in circadian rhythms in metabolic or-
gans such as the liver, leading to the development and maintenance of
metabolic disease. A similar scenario is observed in simulated shift
work conditions. For example, simulated shift work conditions in mice
fed a standard laboratory diet led to the development of fatty liver to
the same extent as mice fed a high fat diet [150]. Time-restricted
feeding protocols offer a mechanism to realign and reinforce circadian
rhythms and have been shown to offer significant protection from diet-
induced obesity and associated metabolic diseases [151]. In addition,
time-restricted feeding has been shown to prevent obesity induced by
chronic advances of the light/dark cycle in mouse models of jet-lag and
shift work [152]. Further, time restricted feeding has been shown to
entrain circadian clock-related mechanisms, including behavior, se-
cretion of hormones, body temperature, and clock gene expression in
the periphery [153]. The benefits of time-restricted feeding on meta-
bolic processes, heart and brain health has been covered in details in a
review by Chaix et al. [149]. This review will focus on the effects of
time-restricted feeding on food anticipatory activity and appetite reg-
ulation.
4.1.1. Time-restricted feeding and the anticipation of food intake
It has been shown that during time-restricted feeding there is an
increase in locomotor activity and body temperature 2-3 h before the
availability of food, suggesting that mice anticipate feeding time
through an internal time keeping mechanism known as the food-en-
trainable oscillator (FEO) system [153]. The exact location of the FEO is
unknown, but brain lesion and transgenic mouse studies have revealed
some of the mechanisms involved in the FEO.
Although the SCN and peripheral tissue clocks use the circadian
timekeeping mechanism, described above, there is increasing evidence
A.J. Page, et al.
that the FEO does not require these feedback loops. For example, a
recent study has demonstrated that time restricted feeding can override
otherwise compromised rhythms in various clock gene mutant mice
leading to improvements in metabolic health [154]. Studies have
shown that Clock mutant mice display food anticipatory activity during
restricted feeding protocols [155,156]. In addition, mice deficient in
the clock gene Cryptochrome still displayed food anticipatory activity
even when the SCN was disabled (SCN-lesion or housing in constant
darkness) [157]. Similar observations have been made with Per1-3
single, double and triple knockout mice [158–162], although there are
some discrepancies in the literature regarding Per2 [163]. Despite the
fact that the SCN is not critical for FEO timekeeping, several studies
have shown that circadian clock genes modulate food anticipatory ac-
tivity. There is evidence to indicate that the SCN inhibits anticipatory
behavior with SCN-lesioned mice exhibiting stronger anticipatory ac-
tivity than control mice [164,165]. Further, in mice lacking functional
NPAS2 there was delayed food anticipatory activity [166] and the
period of the FEO rhythm was shorter in Per 1-3 triple knockout mice
[160]. The SCN receives feeding-related information, possibly from the
FEO, and SCN neural output has been shown to be decreased before and
during daytime feeding when neural activity is usually high [167]. In
addition, SCN neurons are glucose sensitive, with glucose phase shifting
the neural activity of cultured SCN slices [168]. Therefore, although the
expression of the clock genes in the SCN is closely linked to the
light:dark cycle, the SCN does sense the nutritional status of the body
and influence food anticipatory activity.
Mice with disrupted dopamine signaling in the striatum do not de-
monstrate normal food anticipatory activity. Dopamine is involved in
reward seeking behavior [169] and dopamine deficient mice do not
forage for food [170]. Mice co-treated with dopamine D1 and D2 re-
ceptor antagonists exhibited reduced food anticipatory activity [171].
Conversely, mice developed food anticipatory activity in response to
timed treatment with a dopamine D1 receptor agonist [172]. Further,
mice lacking a functional D1 receptor exhibited reduced food antici-
patory activity compared to wildtype controls [165,172], an effect not
observed in D2 knockout mice [172]. Together this data suggests that
reward regulation in the striatum, through dopamine signaling, med-
iates food anticipatory activity.
A number of hormones or peptides could also be involved in the
modulation of food anticipatory activity. Studies indicate that feeding
regulation centres in the DMN and ARC, through the action of neuro-
peptides such as ghrelin and orexin [164,173-175], might play a role in
the food anticipatory activity. However, there is a study, using thermal
DMN lesions, which demonstrated that the DMN is not necessary for
food anticipatory activity [176]. Plasma ghrelin levels increase prior to
a meal and ghrelin activates dopaminergic reward pathways in the
brain [177,178]. Ghrelin receptor knockout mice and rats treated with
a ghrelin receptor antagonist exhibit reduced food anticipatory activity
during restricted feeding protocols compared to controls
[174,179,180]. Conversely, preproghrelin (precursor for ghrelin) defi-
cient and ghrelin deficient mice displayed normal food anticipatory
activity in response to restricted feeding protocols [181,182]. There-
fore, although ghrelin may modulate food anticipatory activity it is not
essential for this activity to occur. Food anticipatory behavior might
also involve the orexin signaling pathway. Orexin A and B are neuro-
peptides that regulate arousal [183]. In orexin mutant mice, food an-
ticipatory locomotor activity (not body temperature) was reduced
compared to wildtype controls [184,185]. In contrast, another study
demonstrated food anticipatory activity was unchanged in orexin
knockout mice [181]. Therefore, orexin may play a modulatory role in
food anticipatory behaviour but is unlikely to be critical for this an-
ticipatory activity to occur.
4.1.2. Time restricted feeding and appetite regulation
Experiments, both in animals and humans, have shown there is a
circadian drive to appetite and hunger. In humans, under a constant-
6
Physiology & Behavior 220 (2020) 112873
routine paradigm, there is a trough in hunger during the morning (~8
am) which rises in the afternoon, with a peak in hunger in the evening
(~8 pm) [37]. In rodents, exposed to a light-dark cycle or constant
darkness, feeding rhythms align with the onset of activity in the evening
[186]. However, in mice with a point mutation in the clock gene Per1
there was a disconnect between the feeding pattern and activity, with
the commencement of feeding occurring a few hours before the normal
feeding time of wild-type mice [186]. This suggests that the drive to eat
is independent of daily rhythms in activity.
In terms of food intake regulation, it has been shown, at the mole-
cular level, that time-restricted feeding reinforces the circadian rhythms
in AgRP/NPY neurones, known to promote food intake, in the mouse
hypothalamus [187]. In addition, the loss of diurnal rhythms in gastric
vagal afferent satiety signaling in high fat diet-induced obesity was
prevented by time restricted feeding [188]. It remains to be determined
whether a time restricted feeding protocol can reverse the loss of
diurnal rhythms in vagal afferent satiety signaling observed in high fat
diet-induced obesity [88] and simulated shift work conditions [89]. In
humans, it has been shown that early (0800–1400 h) time restricted
feeding reduced appetite; making hunger more even-keeled, increasing
feelings of fullness and decreasing the desire to eat [189]. This was
associated with a decrease in the mean levels of the hunger hormone
ghrelin and an increase in the satiety hormone PYY [189]. Further, in
humans limiting food intake to a 8–11 h period during the daytime
[141,190, 191] or eating a large breakfast and small dinner [192–194]
decreased appetite and/or food intake. It remains to be determined
whether a time restricted protocol for a limited number of days per
week, allowing for a more relaxed weekend lifestyle, will provide suf-
ficient entrainment to maintain oscillations in appetite regulation on
the days when the time restricted feeding protocol is not being fol-
lowed.
5. Conclusion
The circadian system plays an important role in the temporal reg-
ulation of metabolic processes, such as anabolism and catabolism, and
food intake to increase energy efficiency. In conditions such as high fat
diet-induced obesity or shift work there is a disruption in circadian
rhythms and food intake patterns leading to a misalignment in meta-
bolic processes and the development and/or maintenance of the obese
state. It is still unclear whether the disruption in circadian clocks is
causing the disruption in food intake patterns or vice versa but it is clear
that the timing of food intake is a strong zeitgeber regulating many
peripheral clocks, particularly in the gastrointestinal tract. Therefore,
time restricted feeding provides a mechanism by which circadian clocks
can be realigned. In addition, time restricted feeding has the capacity to
realign the circadian and FEO system maximising efficiency of food
intake, digestion and absorption in line with metabolic processes.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.physbeh.2020.112873.
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