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Annual Review of Nutrition

Time-Restricted Eating to
Prevent and Manage Chronic
Metabolic Diseases
Amandine Chaix,1,∗ Emily N.C. Manoogian,1,∗
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Girish C. Melkani,2 and Satchidananda Panda1

1
Regulatory Biology Lab, Salk Institute for Biological Studies, La Jolla, California 92037,
USA; email: [email protected]
2
Molecular Biology Program and Heart Institute, Department of Biology, San Diego State
University, San Diego 92182, California, USA

Annu. Rev. Nutr. 2019. 39:12.1–12.25 Keywords

The Annual Review of Nutrition is online at
time-restricted feeding, time-restricted eating, metabolic disease, circadian
nutr.annualreviews.org
rhythms
https://doi.org/10.1146/annurev-nutr-082018-
124320 Abstract
Copyright © 2019 by Annual Reviews.
Molecular clocks are present in almost every cell to anticipate daily recur-
All rights reserved
ring and predictable changes, such as rhythmic nutrient availability, and
∗
These authors contributed equally to this article
to adapt cellular functions accordingly. At the same time, nutrient-sensing
pathways can respond to acute nutrient imbalance and modulate and
orient metabolism so cells can adapt optimally to a declining or increasing
availability of nutrients. Organismal circadian rhythms are coordinated
by behavioral rhythms such as activity–rest and feeding–fasting cycles to
temporally orchestrate a sequence of physiological processes to optimize
metabolism. Basic research in circadian rhythms has largely focused on the
functioning of the self-sustaining molecular circadian oscillator, while re-
search in nutrition science has yielded insights into physiological responses
to caloric deprivation or to specific macronutrients. Integration of these
two fields into actionable new concepts in the timing of food intake has led
to the emerging practice of time-restricted eating. In this paradigm, daily
caloric intake is restricted to a consistent window of 8–12 h. This paradigm
has pervasive benefits on multiple organ systems.

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Contents
INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2
THE MOLECULAR CIRCADIAN CLOCK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.4
NUTRIENT-SENSING PATHWAYS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.4
CROSS TALK BETWEEN THE CIRCADIAN OSCILLATOR
AND NUTRIENT-SENSING PATHWAYS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.6
THE INTERACTION BETWEEN CIRCADIAN RHYTHMS AND
FEEDING–FASTING CYCLES DRIVES ROBUST OSCILLATIONS . . . . . . . . 12.7
CIRCADIAN RHYTHM DISRUPTION: CAUSE, FACILITATOR,
OR EFFECT OF METABOLIC DISEASE? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.8
TIME-RESTRICTED FEEDING AND TIME-RESTRICTED EATING . . . . . . . . 12.8
TIME-RESTRICTED FEEDING OR EATING AND LIVER FUNCTION . . . . . 12.10
Time-Restricted Feeding/Eating and Control of Blood Glucose Levels . . . . . . . . . . . 12.10
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Time-Restricted Feeding and Lipid Metabolism in the Liver . . . . . . . . . . . . . . . . . . . . . 12.12

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Time-Restricted Feeding and Cholesterol Metabolism in the Liver . . . . . . . . . . . . . . . 12.13

TIME-RESTRICTED FEEDING/EATING AND ADIPOSE
TISSUE FUNCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.13
TIME-RESTRICTED FEEDING AND HEART HEALTH . . . . . . . . . . . . . . . . . . . . . . 12.14
TIME-RESTRICTED FEEDING/EATING AND GUT HEALTH . . . . . . . . . . . . . . 12.15
TIME-RESTRICTED FEEDING AND BRAIN HEALTH . . . . . . . . . . . . . . . . . . . . . . .12.16
PERSPECTIVE ON THE FUTURE OF TIME-RESTRICTED EATING . . . . . . . 12.17

INTRODUCTION
The quality and quantity of nutrition are well-accepted determinants of health. However, recent
progress in the field of circadian rhythms has led to the idea that the time of day when food is
ingested affects body weight, body composition, glucose regulation, lipid homeostasis, the gut
microbiome, cardiac function, inflammation, sleep, and overall health (90). Daily fluctuation in
nutrient absorption, assimilation, substrate interconversion, and utilization are lending increasing
support to this concept (Figure 1).
Circadian rhythms are ∼24-h rhythms in biological processes that are produced by endoge-
nous circadian clocks. The circadian clock in animals is based on a cell-autonomous transcription–
translation feedback circuit composed of nearly a dozen transcription factors and more than 50
accessory proteins (90). The circadian clock regulates nutrient utilization at the cellular level
through clock transcription factors that modulate the expression of many downstream genes in-
volved in nutrient utilization, and at the behavioral level, it also regulates ingestion, through circa-
dian rhythms in activity–rest cycles and the dependent rhythm in feeding–fasting (9). Feeding and
fasting are also known to acutely activate nutrient-sensing pathways that act at both the transcrip-
tional and posttranscriptional levels to maintain cellular and organismal nutrient homeostasis (24).
Circadian clock components interact with nutrient-sensing pathways, and this interaction
serves three major functions: (a) When feeding occurs at an anticipated time, the integrated an-
ticipatory response, driven by the circadian clock, and an acute response, initiated by nutrient-
sensing pathways, act synergistically to maintain nutrient homeostasis; (b) when feeding occurs
at an unanticipated time, the nutrient-sensing pathways act on the circadian clocks to adjust the
phase of the clocks, so that on the subsequent days, food is anticipated at the new feeding time;

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Rhythmic behavior Balanced metabolic functions

Hunger
Activity Rest
Energy
utilization

Excretion
Digestion

Energy
storage
Feeding Fasting

Satiety

Coordinated response
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Molecular oscillations
Brain
Neurotransmitters
Muscle Salivary
glands
Gene networks Hormones

Adipose Digestive
tissue tract Proteins Enyzmes

Posttranslational
modifications Metabolites
Liver Microbiome

Redox state

Pancreas

Figure 1
The extensive roles of the circadian clock in regulating nutritional and energetic balance, from behavior to molecules. The master clock
controls daily rhythms in activity–rest and associated feeding–fasting behaviors. Accordingly, metabolic functions oscillate between
nutrient digestion and energy storage during satiety and between nutrient excretion and energy mobilization during hunger. This
nutritional and energetic equilibrium engages multiple organs to ensure balanced digestion and excretion (for example, the salivary
glands, pancreas, digestive tract, microbiome, liver) and balanced energy storage and utilization (for example, the liver, muscle, adipose
tissue). The secretion of digestive enzymes and hormones, as well as gut peristalsis also vary during the day. At the molecular level,
metabolic rhythms are associated with daily oscillations in the activity of gene networks, protein expression, posttranslational
modifications, the level of metabolites, and redox state. The master clock and peripheral clocks play critical roles in the daily temporal
coordination of these processes.

(c) circadian regulation ensures that the appropriate pathways that help assimilate nutrients begin
to rise in anticipation of feeding, so that the organism can better handle a rush of nutrients. How-
ever, this circadian clock–driven rise in gene expression that optimizes nutrient utilization declines
after a few hours. During this decline or at its nadir, feeding can activate nutrient-sensing path-
ways separate from the circadian system, but the suboptimal expression of circadian-driven genes
compromises how the food is processed. In sum, this interaction defines a limited time window
for optimal nutrient metabolism. Accordingly, time-restricted feeding (TRF) or time-restricted

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eating (TRE, when referring to humans), in which food is consumed within a consistent 8–12-h
interval appears to sustain optimal nutrient utilization and promote health (90). The concept of
TRF and its molecular correlates are being extensively studied in animal models, and human stud-
ies of TRE are beginning to emerge.

THE MOLECULAR CIRCADIAN CLOCK

Circadian timekeeping mechanisms are present in almost every brain region and peripheral organ
implicated in nutrient metabolism, including hunger, digestion, absorption, substrate interconver-
sion, utilization and storage, detoxification, and excretion (Figure 1).
At the molecular level, circadian rhythms arise from a cell-autonomous feedback circuit driven
by the bHLH (basic helix-loop-helix)-PAS transcription factors BMAL1 (also known as ARNTL
or MOP3) and CLOCK, or the CLOCK homolog NPAS2 (for simplicity, this review utilizes
CLOCK/BMAL1, when referring to all heterodimer forms). In this circuit, CLOCK/BMAL1
heterodimers bind to target E-box site (CACGTG) elements present in the promoter regions
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of the period (PER1 and PER2) and cryptochrome (CRY1 and CRY2) genes to activate their tran-
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scription. In turn, the PER and CRY proteins heterodimerize to inhibit CLOCK/BMAL1 activity,
thus producing ∼24-h rhythms in PER and CRY transcription. In addition, CLOCK/BMAL1 and
PER/CRY generate rhythmic transcription of the ROR and REV-ERB classes of nuclear hormone
receptors, whose opposing actions on the BMAL1 promoter result in an ∼24-h rhythm in BMAL1
transcription (reviewed in 97, 117). This self-sustained oscillation persists in the absence of any
external timing cues, such as food or light, thus offering the organism an intrinsic timing system
(Figure 2).
While circadian rhythm research began with the search for the autonomous 24-h timekeeping
mechanism that is self-sustaining in the absence of periodic cues, such as light–dark or feeding–
fasting events, in the natural world, daily rhythms are a function of the circadian clock and inter-
locked environmental and behavioral rhythms. Therefore, it is equally important to understand
how light–dark and feeding–fasting cycles interact with the circadian clocks that ultimately dictate
the daily rhythms in behavior, physiology, and metabolism.
The suprachiasmatic nucleus (SCN) of the hypothalamus acts as the master circadian clock.
Developmental or acute surgical ablation of the SCN completely abolishes activity–rest rhythm
and almost all physiological rhythms (127). The SCN uses both synaptic and diffusible factors to
synchronize circadian clocks in other brain regions and peripheral organs. The SCN is monosy-
naptically innervated with intrinsically photosensitive and melanopsin-expressing retinal ganglion
cells (50). The intrinsically photosensitive retinal ganglion cells constitute the principal conduit
for light entrainment of the master circadian clock in the SCN (45, 47). Melanopsin photopigment
is most sensitive to blue light, and the circadian activity–rest rhythm as well as light suppression
of the sleep-promoting hormone melatonin are also most sensitive to blue light (48). Accord-
ingly, chronic exposure to white light or blue-spectrum-enriched light or frequent changes in
light exposure pattern from one day to another—as occurs during shift work or travel across time
zones—can disrupt the normal functioning of the master circadian oscillator and have systemic
circadian disruptive effects. While the effects of light on circadian rhythms are well studied, there
is emerging evidence that the timing of food ingestion also has a profound impact on circadian
clocks in peripheral organs and in some brain regions.

NUTRIENT-SENSING PATHWAYS
In mammals, feeding behavior is cyclic with periods of fasting separating feeding bouts. Accord-
ingly, nutrient metabolism, from individual cells to the whole organism, has adapted mechanisms

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Bmal1
RRE
REV-ERBα/β RORα/β/γ
PER1/2 CRY1/2
BMAL1 CLOCK
Ccg
E-Box

NUCLEUS C YTOPLASM
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Diurnal primates and humans Nocturnal mice and rats

b
Melatonin
Cortisol/corticosterone
Hormones

Growth hormone
Ghrelin
Leptin
Glucagon Not rhythmic Not rhythmic HIGHER

Insulin
Clock components Liver metabolic

Insulin/AKT/mTOR
regulators

No data
AMPK No data
CREB No data
SREBP No data

REV-ERBβ
REV-ERBα
in the liver

Bmal1
Cry1
Cry2
Per2
Per1

Figure 2
From molecular circadian oscillations to daily rhythms in metabolic regulators. (a) Representation of the core cell-autonomous
circadian transcriptional–translational feedback loop. Activators are depicted in blues and repressors in red. (b) Schematic of the daily
peak of clock components (messenger RNA expression), liver metabolic regulators (pathway activity), and hormones (serum level)
both in diurnal primates and humans and nocturnal mice and rats. Abbreviations: AKT, protein kinase B; AMPK, adenosine
monophosphate–activated protein kinase; CREB, cyclic adenosine monophosphate response element binding protein; Ccg:
clock-controlled genes; mTOR, mammalian target of rapamycin; SREBP, sterol regulatory element binding protein.

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to switch between nutrient storage during periods of availability and the use of stored nutri-
ents during periods of fasting. Elaborate regulatory pathways (neuroendocrine, cellular signal-
ing, substrate-mediated enzymatic control) have evolved to sense nutrients or energy status and
to cycle between anabolic and catabolic states to maintain homeostasis. Such cycles apply to car-
bohydrate, fat, and protein metabolism. For example, glycogen synthesis or glycogenolysis (and
gluconeogenesis), fatty acid synthesis or β-oxidation, and protein synthesis and amino acid degra-
dation exhibit daily rhythms (9, 10). The metabolism of cholesterol and nucleotides are interlocked
within the metabolism of carbohydrate, fat, and protein.
Several key metabolic sensors, regulators, and effectors have been identified. Genetic inacti-
vation of these components disrupts one or multiple steps in the anabolic or catabolic arm of
the normal metabolic cycle and eventually leads to metabolic diseases. These molecules range
from (a) endocrine regulators, hormones such as insulin or glucagon, to (b) cell-autonomous
signaling modules, such as the insulin receptor and adenosine monophosphate (AMP)-activated
protein kinase (AMPK) signaling pathways, to (c) transcriptional regulators, such as peroxisome
proliferator–activated receptor-gamma (PPARγ), PPARγ coactivator 1-alpha (PGC1α), liver X
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receptor (LXR) and retinoid X receptor (RXR) to (d) enzymes, such as phosphoenolpyruvate car-
boxykinase (PCK1), glucokinase (GCK), fatty acid synthase (FAS), and cytochrome P450 family
7 subfamily A member 1 (CYP7A1). Unlike the self-sustained circadian oscillator, the expression
or activity of these metabolic regulators is dampened or arrhythmic under prolonged fasting in
whole animals or in tissue culture cells (52, 125). However, these regulators respond to feeding or
fasting in a manner comparable to that of a switch or an hourglass (reviewed in 13). For example,
in response to feeding and consequent insulin signaling, protein kinase B (AKT) phosphorylation
aligns with the period of feeding, while glucagon signaling during fasting drives cAMP response
element binding (CREB) protein phosphorylation and targets gene transcription (125) (Figure 2).

CROSS TALK BETWEEN THE CIRCADIAN OSCILLATOR

AND NUTRIENT-SENSING PATHWAYS
Nutrient-sensing pathways can impact the circadian clock, so the clock can be entrained to changes
in the timing of nutrient availability (27, 114). Conversely, the circadian system also modulates
nutrient-sensing and -response mechanisms, such that responses to feeding or fasting at pre-
dictable times are amplified.
The circadian system and nutrient-sensing pathways interact at multiple levels, from the whole
organism to individual molecules. At the molecular level, clock and metabolic regulators interact
at multiple nodes. For instance, both CRY and BMAL1 are involved in the coupling between
nutrient pathway and the clock. The clock protein CRYs also function as repressors of glucocor-
ticoid receptor–mediated transcription (62). Mice lacking Cry exhibit overexpression of glucocor-
ticoid receptor target genes, including Pck1, and consequently display impaired glucose tolerance.
CRY proteins also exhibit extranuclear roles in repressing the function of the metabolic regulator
CREB (134). Consequently, acute knockdown of Cry in hepatocytes and Cry knockout hepatocytes
show elevated expression of the gluconeogenic CREB target glucose 6-phosphatase (134). Acute
knockdown of Cry in the liver elevates fasting plasma glucose levels, while acute overexpression
suppresses gluconeogenesis (134). Bmal1 is induced and required for adipocyte differentiation in
vitro (111). The BMAL1 protein is found at the promoter of several genes involved in lipid and
sterol biogenesis pathways, and its phase of expression coincides with the increased expression
of genes including sterol regulatory element binding transcription factor 1 (Srebf1), Fasn, cluster
of differentiation 36 (Cd36), acetoacetyl-coenzyme A (CoA) synthetase (Aacs), and 3-hydroxy-3-
methylglutaryl-CoA reductase (Hmgcr) (60, 100). Additionally, the cellular energy sensor AMPK

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phosphorylates and tunes the degradation of CRY proteins, which in turn modulates the repres-
sion of CLOCK/BMAL1-mediated transcription of the target genes (63). CLOCK/BMAL1 mod-
ulates the transcription of key components of the AMP salvage pathway and imposes rhythms on
cellular levels of nicotinamide adenine dinucleotide (NAD) (84, 96). NAD levels modulate activ-
ities of the NAD-dependent poly(ADP-ribose) polymerase enzymes and sirtuins that impact the
circadian oscillator (8, 83). Feeding itself causes changes in core body temperature and activates
heat shock factor 1, which upregulates Per2 transcription (98). Additional cross talk through the
mammalian target of rapamycin (mTOR), glycogen synthase kinase, casein kinase, many nuclear
hormone receptors, and their coactivators has also been demonstrated (reviewed in 14). This ex-
tensive cross talk imposes three principal temporal regulations: (a) The circadian clock gates the
cellular responses to feeding and fasting; (b) fasting duration and feeding bouts impact the oscil-
lator and change its robustness; and (c) the interaction between the temporal feeding pattern and
the clock determines the global transcriptional adaptation to energy availability.
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THE INTERACTION BETWEEN CIRCADIAN RHYTHMS AND

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FEEDING–FASTING CYCLES DRIVES ROBUST OSCILLATIONS

Although the cell-autonomous circadian oscillator can sustain transcriptional oscillations under
constant environmental and nutrient conditions, robust genome-wide transcriptional rhythms in
intact animals arise from interactions between the circadian clock and feeding–fasting cycles. For
example, in the liver of fasted mice, a smaller number of transcripts, including the clock compo-
nents, and their direct output targets oscillate with 24-h rhythms. When mice are fed a normal
chow ad libitum, they consume the majority of their calories at night and a smaller fraction dur-
ing the day, and their liver shows rhythmic expression of a relatively large number of transcripts.
Consolidating feeding to ∼8 h without altering caloric intake further increases the number of
rhythmic transcripts to a few thousand protein-coding genes. In the absence of a circadian clock,
as in Cry1−/− ;Cry2−/− mice, the feeding rhythm is abolished, and the liver transcriptome does not
show any significant rhythm. However, consolidating feeding to ∼8 h drives rhythmic transcrip-
tion of a few hundred transcripts in the liver, including downstream targets of CREB, activating
transcription factor 6 (ATF6), mTOR, forkhead box protein O (FoxO), and PGC1α. Furthermore,
consistent feeding during the daytime phase shifts peak expression levels of most liver rhythmic
transcripts by 12 h relative to those in mice fed mostly at night, suggesting that the hepatic cir-
cadian transcriptome is largely driven by the time of feeding (125). Similarly, daily rhythms in
levels of protein and metabolites are also found in circadian mutant mice subject to a defined
feeding–fasting cycle (2, 11, 86).
The relevance of the effect of food on the circadian system has also been examined in mod-
els resembling human shift work. In a rodent model of shift work in which mice are forced to
be active during the day (when they would normally sleep) on weekdays and allowed to sleep
and eat when they like on weekends (105), an increase in daytime food consumption is observed
during weekdays. This paradigm dampens the global gene expression rhythm in the liver (12),
which roughly resembles the dampened gene expression rhythm found in mice fed a high-fat diet
ad libitum (59). Together, these results indicate that (a) feeding consolidation reinforces diurnal
rhythms in thousands of hepatic transcripts; (b) the temporal spreading of caloric intake and an ir-
regular feeding schedule, as found in shift work, dampens diurnal rhythms; (c) the feeding–fasting
cycle can drive the rhythmic expression of hundreds of hepatic transcripts even in the absence of
a circadian oscillator; and (d) consistent daytime feeding in mice can drive robust transcriptional
oscillations with phases that are ∼12 h away from those of animals fed during the night. These
observations suggest that consistent feeding during the day in nocturnal animals may still sustain

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robust diurnal oscillations. Such eating patterns in animals have shown attenuation of metabolic
diseases commonly found among shift workers (109).

CIRCADIAN RHYTHM DISRUPTION: CAUSE, FACILITATOR,

OR EFFECT OF METABOLIC DISEASE?
The intimate interaction among circadian clock, light–dark and feeding–fasting cycles implies that
an inconsistent duration of light exposure or a change in eating time from one day to another can
disrupt daily rhythms. Additionally, in humans, reduced sleep can also indirectly affect circadian
rhythms, as sleep deprivation increases the probability of consuming an energy-dense diet (73)
and prolongs exposure to lighting, both of which disrupt circadian rhythms. Therefore, circadian
rhythm disruption (CRD) can be defined as a misalignment in the timing of and/or change in the
duration of ambient illumination, sleep, and period of eating from a reference range. Because the
impact of food and light on circadian rhythms in humans has only recently been documented, it
is too early to come to a consensus around the reference timing and duration for light exposure,
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sleep, and nutrition that sustain robust circadian rhythms. Nevertheless, with sleep duration as a
relatively better agreed-upon reference value (51, 89), an ideal circadian day for an average adult
would involve (a) 8 h for sleep, (b) waiting for at least 1 h after waking up before the first caloric
intake of the day, (c) at least 1 h of exposure to bright light (1,000–10,000 lux) within the first half
of the waking hour to entrain the hypothalamic clock to ambient light and to suppress melatonin
(131), (d) exposure to dim or blue-depleted light for 2–3 h prior to bedtime to build sleep pressure,
and (e) no caloric ingestion for 2–3 h prior to bedtime. As the wake-up time in humans is closely
linked to light exposure, an abrupt change in the habitual wake-up time or bedtime by ≥2 h can
disrupt normal circadian rhythms. Subjectively, most individuals also experience the discomfort
of 2 h of jet lag after traveling across two time zones within a day.
Shift workers, who account for ∼20% of the workforce worldwide, experience chronic cir-
cadian rhythm disruption. Even those who do not work shifts tend to change their weekday and
weekend sleep and eating patterns, and some studies have estimated that nearly 80% of the general
population experiences social jet lag (129). Actual shift work and chronic CRD under experimental
conditions that mimic shift work or social jet lag can increase risks for noninfectious chronic dis-
eases, including glucose intolerance, weight gain, adiposity, liver diseases, various forms of cancer,
depression, and cardiovascular diseases, among others (3, 30, 57, 76, 81, 108, 124). Chronic CRD
also compromises the immune system so that experimental animals become more susceptible to
elevated inflammation and septic shock (29). As these chronic diseases now account for more than
85% of healthcare cost in the United States (19), experimentally testing the effect of circadian
rhythm optimization by improving patterns of light exposure, sleep, and caloric intake to prevent
and better manage these diseases will lead to significant impacts on public health. Among these
three factors, the daily timing of nutrition is an attractive target as it can complement the rich
scientific knowledge and public health infrastructure that are based on the impact of nutrition
quality and quantity on health and disease.

TIME-RESTRICTED FEEDING AND TIME-RESTRICTED EATING

The concepts of TRF in animals and TRE in humans arose from studies examining the effects
of food timing on the circadian system. The idea was to restrict feeding to a certain time of the
day or night and test how this restriction affected daily rhythms in activity–rest cycles and clock
components in metabolic organs (primarily the liver). The initial TRF experiments were done in
rodents by restricting the timing of food access to a few hours (typically 4–8 h) during the day,

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when rodents usually rest and eat less, and then testing whether the daily activity–rest cycle would
follow the new eating routine (36, 78). Restricting the time of food access to less than 8 h often
reduces caloric intake. These experiments showed that rodents would wake up a few hours prior
to the arrival of food and start ambulatory activity as if they were anticipating food. Such food
anticipatory activity also occurred when calories were reduced and presented at night, and the
magnitude of activity increased with the reduction in calories (79). Therefore, caloric restriction
(CR) did not compromise physical activity, rather it increased the opportunistic food-seeking
behavior that is important for survival (22, 25). In parallel, these TRF experiments also revealed
that daytime access to food changed the phase of the circadian clock components in the liver of
mice, such that clock components whose expression typically rises at night, instead rose during
the day and vice versa (27, 114). Therefore, it was concluded that the liver clock is largely driven
by the timing of food intake and not by the SCN clock, whose phase is tied to the light–dark cycle.
Conversely, in rodent models of diet-induced obesity, in which mice are given ad libitum access
to a high-fat and high-sucrose diet, the daily feeding rhythm dampens and mice distribute their
caloric intake throughout the 24-h day. This eating pattern also dampens the liver’s circadian clock,
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and it systemically affects almost all of the circadian transcriptome, both in metabolic organs and
the brain (59). To test the relative contribution of an obesogenic diet and the disrupted eating
pattern to obesity and metabolic diseases in these mice, we and others have subjected mice to
isocaloric food consumption from a high-fat and high-sucrose diet at 8–12 h intervals. The rodents
that eat the same calories from the same food source as the ad libitum cohort are largely protected
from high-fat diet-induced obesity and related metabolic illnesses (21, 23, 49, 109, 133).
The initial rodent experiments were done with 8 h access to food and, hence, a popular diet
called the 8-h diet or 8:16 diet arose. In popular media, it is also grouped under the umbrella
of intermittent fasting, which describes all types of fasting, lasting from a few hours to a few
days, without any explicit reference to circadian rhythms. Subsequently, TRF of 8–12 h without
reducing caloric intake in rodents was shown to prevent obesity and diseases in a dose (fasting-
duration)-dependent manner, with 8-h TRF having maximum benefits and 12-h TRF having less
benefit (23). TRF in daytime also shows some benefit for weight loss relative to ad libitum controls
(109). There is some debate about whether daytime TRF and nighttime TRF offer the same
benefits in mice because daytime TRF has shown slightly reduced benefits in some experiments
(7). Daytime TRF in rodents disturbs their habitual sleep and also temporally decouples their
normal physical activity, which is aligned with feeding time (95). Therefore, it is not clear whether
it is the direct effect of daytime TRF or an indirect effect of sleep loss and lack of physical activity
after consuming a meal that contributes to the slightly attenuated benefits of daytime TRF in
mice.
Many CR studies in rodents are done in a manner that also imposes time restriction in feeding.
Traditionally, in CR studies control mice receive food ad libitum while the CR mice are given a
meal at a fixed time each day that contains 20–30% fewer calories. The mice typically consume
the reduced calories within 2–3 h, leaving a prolonged 20–22 h fasting interval (1, 80). Other
rodent CR experiments have been done in which the CR cohort received the food in the morning,
afternoon, or evening. However, irrespective of the timing of the calorie-restricted diet, all of these
experiments extended the life span (85). In short-term studies, however, CR mice receiving food in
the morning (when they are supposed to be sleeping) had less weight loss than mice that received
the same calories at night (1). In a recently concluded controlled experiment designed to test the
effect of time of meal in CR experiments, when the control mice were also given the daily ration at
a fixed time, they finished the food within 10–12 h. These mice also lived longer than the control
ad libitum–fed mice but shorter than the CR mice (80). This raises the idea that some benefits of
CR also arise from time restriction (31).

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Human studies on the timing of diet and health outcomes with respect to circadian physiology
have a relatively long history. For more than 30 years it has been well known that in response to
a standard test meal, postprandial glucose remains relatively higher in the evening or late night
than in the morning (115, 123). This also fits with the action of circadian rhythms in insulin
release and the suppressive effect of the sleep hormone melatonin on insulin release (92, 110,
122). Together these effects suggest that consuming a bigger portion of daily caloric intake during
the first half of wakeful hours may be preferred for better blood glucose regulation and weight
control. Accordingly, it is likely that the reports of breakfast skipping having detrimental health
effects also ignored that those skipping breakfast might have had late-night eating events (20),
so the causal link between breakfast skipping and health outcomes remains inconclusive (113).
Relatively recent studies of caloric reduction interventions in humans have retrospectively found
greater weight loss if lunch is consumed earlier rather than later (41). Epidemiological studies on
the timing of food intake or length of overnight fasting on health outcomes are also emerging.
These studies are revealing that a prolonged overnight fast of 13 h or longer, or eating an earlier
dinner, correlates with a reduced risk for cancer (58, 72).
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A big difference between laboratory rodents and humans is the production of melatonin and
its effect on glucose homeostasis. Most laboratory mouse strains, specifically the widely used
C57BL/6J strain, do not produce melatonin. In humans, melatonin levels in the plasma or saliva
begins to rise 2–3 h before habitual bedtime (99). A receptor for melatonin, melatonin receptor 1B
(MTNR1B), is expressed in insulin-producing pancreatic islets. The binding of melatonin with
its receptor in these cells leads to the attenuation of glucose-stimulated insulin release, and this
inhibition is further accentuated in humans carrying a mutant allele of MTNR1B (93). The func-
tional consequence of this interaction is the reduced production of insulin in response to a meal
late at night, which is further worsened in individuals carrying the mutant allele (68). As a result,
carriers of this mutant allele have increased risks for hyperglycemia and type 2 diabetes (16, 71,
102). In summary, this interaction between melatonin and insulin release suggests it may be ben-
eficial to avoid meals for 2–3 h before going to bed and for up to an hour after waking up, after
which melatonin levels decline. Altogether, multiple lines of observation support the notion that
confining all caloric intake to within a defined time interval that is a few hours separated from the
daily sleep interval has multiple health benefits.
The underlying biochemical or gene expression basis for the health benefits of TRF is bet-
ter studied in animal models. In the following sections we discuss mechanisms, with a specific
emphasis on metabolic organs (Figure 3).

TIME-RESTRICTED FEEDING OR EATING AND LIVER FUNCTION

Human metabolic health and the diagnosis of disease are often linked to the metabolism of glucose,
fat, and cholesterol. The liver plays an important role in the metabolism of all three factors. Hence,
we discuss the molecular changes during TRF and TRE that affect these metabolic pathways in
the liver.

Time-Restricted Feeding/Eating and Control of Blood Glucose Levels

Both the hormonal regulation of glucose (glucagon, insulin, and incretins) and cell-autonomous
enzymatic regulation of glucose metabolism are modulated by the circadian clock and nutrient-
sensing mechanisms (90). Time series analyses of gene expression, protein abundance, posttransla-
tional modifications, and levels of metabolites in rodents that undergo TRF have shed light on the
potential mechanisms by which TRE maintains glucose homeostasis. Most of the rodent studies

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Benefits brain health

Reduced ROS levels
Increased integrated
stress response
Improved sleep and
motor coordination
Preserves muscle Counters fatty liver
fitness
Preserved
Improved endurance metabolic rhythms
Increased flight index Reduced steatosis
Preserved metabolic Better cellular defense
efficiency mechanisms

Time-
Reduces heart aging Maintains gut integrity
restricted
Preserved cardiac feeding Preserved rhythms of
contractility vagal afferents
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Increased ETC activity Selection of a

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Improved proteostasis protective microbiome

Protections from
gut permeability

Prevents brown Blocks white

adipose cell whitening adipose cell hypertrophy
Increased fatty acid oxidation Increased lipid turnover
Increased Reduced hypertrophy
mitochondrial content Lower inflammation
Increased UCP
expression

Figure 3
Pervasive benefits of time-restricted feeding. Chronic circadian rhythm disruption is a risk factor for
metabolic diseases. Studies in animal models (flies, mice, rats) and emerging studies in humans show that
time-restricted feeding protects metabolic tissues from metabolic disturbances. Time-restricted feeding may
also benefit brain health and could delay the development of neurodegenerative diseases. Abbreviations:
ETC, electron transport chain; ROS, reactive oxygen species; UCP, uncoupling protein.

have been done in mice fed a high-fat and high-sucrose diet, as this diet accelerates insulin re-
sistance and the effect of any pharmacological or lifestyle intervention can be observed within a
short period of time.
It is known that ad libitum access to a high-fat diet dampens the feeding rhythm and also
dampens the rhythmic expression of many clock components, primarily by reducing peak levels
(59). Conversely, TRF increases the peak expression levels both of activators and repressors of core
clock components, including that of the repressors Cry1, Rev-erbα, and Per2, and of the activator
Bmal1 (49). Core clock components affect metabolism through direct transcriptional regulation or
through modulating signaling or transcription of interacting factors (14). Accordingly, increased
expression of clock components for a few hours every 24 h modulates the expression or function
of several regulators of glucose homeostasis.
Blood glucose is tightly regulated and is maintained within a narrow range. The liver plays an
important role in glucose homeostasis. During the fasting state, the pancreatic hormone glucagon
increases phosphorylation of the transcription factor CREB, which activates downstream target

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genes to promote gluconeogenesis to maintain blood glucose (5, 75). In mice fed a high-fat diet
ad libitum, CREB remains phosphorylated during both the fasted and fed states. CREB phos-
phorylation during the fed state fails to suppress gluconeogenesis when it is not needed, and this
excess gluconeogenesis likely contributes to the elevated blood glucose level. TRF restores the
daily rhythm in CREB phosphorylation, with elevated levels of phosphorylated CREB (pCREB)
during the fasted phase (49). Such rhythmic abundance of pCREB, with reduced pCREB levels
during the fed state, also parallels a reduction in the expression of CREB target genes, which are
implicated in gluconeogenesis. Parallel liver metabolomic analyses have also indicated that TRF
reduces gluconeogenesis, promotes the tricarboxylic acid cycle (TCA), and shuttles glucose toward
the pentose phosphate pathway (49).
The pentose sugars generated by the pentose phosphate pathway and some intermediates of the
TCA cycle are substrates both for the de novo and the salvage pathways of nucleotide biosynthesis.
Accordingly, increased levels of several nucleotides in mice exposed to TRF are also observed (49).
During the fed state, glucose is also utilized for glycogen synthesis. Electron microscopy images
of TRF mouse liver show increased levels of glycogen (49). Overall, these coordinated changes
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in gene expression and metabolites imply that TRF reprograms glucose metabolism away from
gluconeogenesis and toward anabolic pathways.
TRF reduces insulin resistance by an unknown mechanism. Both fasting and postprandial levels
of serum insulin levels are relatively high in mice fed a high-fat diet ad libitum, while TRF reverses
this trend (23, 49). Insulin activates mTOR, which in turn phosphorylates S6 (24, 34). Levels of
phosphorylated S6 (pS6) are typically higher in the fed state or at night. However, mice on ad
libitum feeding of a high-fat diet show an inverted pS6 rhythm, with higher levels during the day.
TRF corrects this temporal activation of pS6 and aligns the higher levels with the fed state (49).
Recent human studies have also shown that TRE can improve cardiometabolic health. TRE
with a 6-h daily interval (from 8:00 a.m. to 2:00 p.m.) for 5 weeks was able to increase β-cell func-
tion and insulin sensitivity and to decrease postprandial insulin, oxidative stress, blood pressure,
and appetite (116). A crossover study in men at risk for type 2 diabetes found that early TRE
(from 8:00 a.m. to 5:00 p.m.) and delayed TRE (from 12:00 p.m. to 9:00 p.m.) improved glycemic
response to a test meal, but only the early TRE led to a decrease in fasting glucose (53).

Time-Restricted Feeding and Lipid Metabolism in the Liver

Both nutrient-sensing pathways and circadian clock components are implicated in hepatic lipid
homeostasis (9, 86). The prolonged fasting in TRF mice mildly elevates hepatic AMP levels, which
in turn activate AMP kinase, one of the key energy sensors of the cell. One of the known targets
of AMPK is acetyl-CoA carboxylase (ACC). ACC catalyzes the carboxylation of acetyl-CoA to
malonyl-CoA, the first and rate-limiting step in fatty acid synthesis. Phosphorylated ACC (pACC)
is enzymatically inactive and, hence, cannot mediate the first step in lipid synthesis. Increased
AMP levels in the liver of TRF mice activate AMPK, which, in turn, phosphorylates ACC, and
this may reduce de novo lipogenesis. TRF also increases the peak expression level of the circadian
clock repressor component Rev-erb. Rev-erb acts as a repressor of several genes implicated in lipid
synthesis (26). Mice carrying the loss-of-function allele of Rev-erb show excessive fat accumulation
in the liver and fatty liver disease (4, 18, 37). Conversely, increased expression of Rev-erb in the
liver of TRF mice parallels reduced expression of its direct target and a key lipogenic gene, Fasn.
Reduced Fasn messenger RNA levels and increased relative pACC levels act synergistically to
reduce fatty acid synthesis, leading to reduced levels of several free fatty acids.
Reduced fatty acid synthesis also promotes fatty acid oxidation. Malonyl-CoA, a product of
ACC activity in the first step of fatty acid synthesis, allosterically inhibits mitochondrial carnitine

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palmitoyltransferase (CPT). CPT is essential for the transit of long-chain fatty acids and acylcar-
nitine esters into the mitochondria for β-oxidation. In the liver of ad libitum–fed mice, elevated
levels of malonylcarnitine imply increased inhibition of CPT and reduced β-oxidation caused by
impaired entry of fatty acids into the mitochondria (49). Conversely, in the liver of TRF mice,
decreased ACC activity reduces malonylcarnitine levels. Although definitive proof of more fatty
acid oxidation in the TRF liver is lacking, the reduced volume of intracellular lipid droplets in
hepatocytes and increased levels of β-hydroxybutyrate, one of the end products of β-oxidation,
in liver from TRF mice relative to liver from ad libitum–fed mice indicate that TRF enhances
lipolysis and β-oxidation, further contributing to a reduction in liver free fatty acids.
A beneficial by-product of reduced fatty acid synthesis and increased β-oxidation is the overall
reduction in the free fatty acid pool in the TRF liver and reduced inflammation. The increased
pool of free fatty acids in the liver of ad libitum–fed mice becomes a substrate for the increased
production of the proinflammatory long-chain n-6 fatty acids dihomo-linoleate (20:2n-6) and
arachidonate (20:4n-6). Liver from ad libitum–fed mice is prone to more oxidative stress as it
contains relatively less reduced glutathione, a major cellular antioxidant. Oxidation of arachi-
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donate and linoleic acid in the liver of the ad libitum–fed mice further increased the levels of
the proinflammatory eicosanoids 15-hydroxyeicosatetraenoic acid (HETE), 5-HETE, and 13-
hydroxyoctadecadienoic acid. In contrast, reduced hepatic lipid levels along with the glutathione-
enriched cellular environment in the liver of TRF mice attenuated the levels of proinflammatory
lipids and reduced the levels of plasma alanine transaminase, a biomarker of fatty liver disease (49).
Histological examination of liver from TRF mice also supports a healthier cellular content and
reduced pathological phenotype. The liver of TRF mice had significantly less hepatic steatosis
compared with the liver from ad libitum–fed mice (49, 109).

Time-Restricted Feeding and Cholesterol Metabolism in the Liver

The mammalian liver synthesizes up to 20% of the whole body cholesterol pool and also reg-
ulates cholesterol break down for the production of bile acids and other sterols (74). Both the
diurnal rhythms in food intake and the clock component Rev-erb are known to affect cholesterol
biosynthesis and break down to bile acids through the transcriptional regulation of several genes,
including Cyp7 (42, 64, 65). The messenger RNA expression of two enzymes at the committing
step of the classical and acidic pathways of bile acid synthesis, Cyp7a1 and Cyp7b1, respectively,
are indicators of cholesterol catabolic activity. Relative to liver from ad libitum–fed mice, the peak
expression of Cyp7a1 was elevated in TRF groups. Additionally, the expression of Cyp7b1 was ele-
vated throughout 24 h in the liver of TRF mice (23, 49). Gene expression of cholesterol anabolic
and catabolic enzymes is also regulated by the transcription factor sterol regulatory element bind-
ing protein (SREBP). Hepatic SREBP was elevated in TRF mice compared with ad libitum–fed
mice. Specifically, the active cleaved form of SREBP was rhythmic, with higher expression dur-
ing the dark–feeding phase in the liver of TRF mice (23). The total active form is reduced in the
liver of ad libitum-fed mice. Together, these changes in Cyp7a1 and Cyp7b1 correlated with a net
increase in the break down of cholesterol, leading to a concomitant reduction in cholesterol and
increase in various bile acids in the liver of TRF mice (23, 49).

TIME-RESTRICTED FEEDING/EATING AND ADIPOSE

TISSUE FUNCTION
Rodents on TRF always exhibit a reduction in adipose tissue mass, while lean mass is preserved
(21, 23, 49, 109). This is also observed among some humans undergoing TRE (82). The difference

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in body weight between ad libitum–fed and TRF groups fed an obesogenic diet for 18 weeks can
be as high as 28%, and most of the difference in body weight is due to a difference in adiposity (21,
23, 49, 109). Gene expression and biochemical studies are largely focused on the liver, and little is
known about molecular changes in adipose tissues. The reduction in adipose tissue mass in obese
mice subjected to TRF suggests that an overall increase in fatty acid oxidation under TRF may
contribute to reduced adiposity in TRF mice.
Both white adipose tissue and brown adipose tissue in mice fed an obesogenic diet ad libi-
tum show hypertrophy and whitening of the brown fat. Conversely, white adipose tissue in TRF
mice has smaller adipocytes, and the brown adipose tissue has more browning, as observed under
hematoxylin and eosin staining of tissue sections (21, 23, 49).
Activation of tissue-resident macrophages is known to increase tissue inflammation and con-
tribute to obesity-related comorbidities. White adipose tissue in TRF mice shows reduced levels
of crown-like structures, which are largely infiltrating macrophages, and a parallel reduction in
many proinflammatory cytokines, including tumor necrosis factor-α, interleukin-6 and chemokine
(C-X-C motif ) ligand 2 (49).
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TIME-RESTRICTED FEEDING AND HEART HEALTH

One of the major adverse outcomes of chronic circadian disruption, as occurs in shift workers, is
an increased risk for cardiovascular diseases (70, 94). In fact, among active duty firefighters, it is the
major cause of death and disability while at work (32, 112). Even among the general population,
cardiovascular diseases remain the number one cause of death worldwide (69). Accordingly, there is
increasing interest in the circadian regulation of heart health. Time series gene expression studies
of the cardiovascular system—including the atrium, ventricle, aorta, and endothelial cells—have
found hundreds to thousands of genes showing circadian rhythms (17, 60, 104). The functional
significance of these rhythms in heart health is clearly demonstrated in various genetic perturba-
tion models (reviewed in 91). For example, Bmal1 knockout mice show increased susceptibility to
atherosclerosis, which may partly arise from systemic metabolic disruption in these mice (103).
The effect of TRF on age-related cardiac decline has been extensively studied in Drosophila.
The Drosophila model has been well established for exploring the genetic basis of the deterioration
of cardiac function that arises due to aging or an energy-dense diet (15, 77, 88, 130). The primary
function of the fruit fly’s heart is to pump hemolymph through the rhythmic diametric expansion
(diastole) and contraction (systole) of the heart tube. By combining semi-intact in vivo prepara-
tion with high-speed imaging, cardiac rhythms can be imaged for a sufficient period of time to
quantitatively assess various cardiac function parameters. TRF of young Drosophila from 2 weeks
of age for 12 h every day did not reduce their daily caloric intake, yet the flies did not gain weight
between 3 and 7 weeks of age, a substantial portion of the lifespan for Drosophila. Ad libitum–fed
flies showed characteristic features of cardiac aging, marked by increases in the diastolic interval,
systolic interval, heart period, and arrhythmia and by reductions in systolic diameter, diastolic di-
ameter, and in radial contractility (43). Both male and female TRF flies exhibited attenuation of
this age-dependent deterioration of cardiac function independent of strain background (43).
Gene expression profiling of head, body, and heart tissues from Drosophila revealed that the
gene expression signature of TRF is distinct from that of CR (38, 43). In the Drosophila heart, TRF
led to downregulation of a cluster of genes encoding for mitochondrial electron transport chains,
which may indirectly reduce reactive oxygen species and protect the heart. TRF also led to a co-
ordinated increase in the expression of various subunits of an adenosine triphosphate-dependent
chaperonin complex (chaperonin containing T-complex protein 1 subunits, or CCT complex) (33,
132). This chaperonin complex is known to facilitate the proper folding of cytoskeletal proteins.

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While CCT complex expression increased in the heart, the expression of genes encoding various
cytoskeletal monomers or subunits actually decreased by as much as 20%. Increased chaperonin
expression coupled with reduced expression of cytoskeleton genes likely reduced the overall frac-
tion of unfolded or misfolded cytoskeletal proteins and improved cardiac function. Genetic per-
turbation of CCT subunits or of mitochondrial electron transport chain components supported
the hypothesis that these changes in gene expression contributed to improved cardiac function in
fruit flies (43). While these experiments are yet to be verified in vertebrates, genome-wide associ-
ation studies have shown that a point mutation in CCT7 is associated with ventricular arrhythmia
(35). Overall, the Drosophila TRF studies have revealed that changes in mitochondrial function
and improvements in proteostasis may underlie some of the benefits of TRF.
Another outcome from the Drosophila TRF experiments was the observation that the TRF
fruit flies showed improved sleep relative to the ad libitum–fed flies flies. Sleep improvement
was seen in flies in group-housed condition, while no difference in sleep in older ad libitum–fed
or TRF flies was found when flies were individually housed (43). Together these observations
suggest that sleep improvement under group-housed condition is not due to changes in overall
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sleep pressure (which remained similar in individually housed flies) but rather to increases in the
arousal threshold. Self-reported sleep improvement is also found in human volunteers undergoing
TRE (44). As sleep improvement also benefits cardiac health, TRE might contribute to improved
heart health both through direct tissue-autonomous mechanisms and indirect system-wide effects
on improving sleep.

TIME-RESTRICTED FEEDING/EATING AND GUT HEALTH

Hunger and satiety operate at a higher level for ingestive behavior and, consequently, for optimal
gut health. Although it may seem reasonable to assume that the daily rhythm of activity–rest cycles
drive the daily rhythm of hunger, experiments both in animals and humans have shown that there
is a circadian drive to hunger, which is likely a product of activity–rest cycles. In a constant-routine
paradigm in humans, hunger rises in the afternoon and peaks in the evening (at about 8:00 p.m.)
(106). Rodents on light–dark cycles or in constant darkness exhibit a feeding rhythm that aligns
with the onset of activity in the evening (or subjective evening). However, mice carrying a point
mutation in the clock gene Per1, exhibit an altered feeding rhythm that is uncoupled from their
activity rhythm (67). These mice begin to eat a few hours before the habitual feeding time of
wild-type mice, but they show no change in their daily activity–rest cycles. Ad libitum access to
food in these Per1 mutant mice renders them obese. However, TRF can prevent excessive obesity
and metabolic disease phenotypes in Per1 mutant mice (67). Such daytime eating behavior in
Per1 mutant mice resembles night-eating syndrome in humans, in which individuals wake up in
the middle of their sleep with extreme hunger and consume a substantial meal (107). Although
this syndrome has not been subject to rigorous genetic analyses, the Per1 mutant mice support
the idea that some eating disorders in humans may have an underlying circadian genetic basis.
Nevertheless, the observation that the metabolic diseases in Per1 mutant mice can be prevented
by TRF offers hope that some of the genetic predisposition to metabolic diseases in humans can
be prevented by a behavioral intervention such as TRE.
Humans exhibit a daily rhythm in the production of saliva, gastric acids, digestive enzymes, and
bile salts, the production of all of which declines late at night. Aligned with the production of these
digestive agents, intestinal peristalsis also shows a daily rhythm, with reduced contractions at night.
Finally, colonic movement increases in the early morning, driving a daily rhythm in excretion (39,
61). With these rhythms in ingestion, secretion, digestion, absorption, and excretion, there is a
daily rhythm in the gut chemical environment. Accordingly, the composition and function of the

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gut microbiome also vary throughout the day (118–120). The nightly rise in growth hormone
from the pituitary works in concert with the nightly rise in mucus secretion and cellular repair
and replication in the gut lining to maintain gut integrity (39, 61). Maintaining intestinal lining
integrity is critical in to support the intestinal barrier function that is essential to prevent potential
food allergens and bacterial lipopolysaccharides from breaching the gut and causing systemic in-
flammation. Although it is too early to measure how TRE affects these gut functions, these daily
rhythms in gut physiology offer a framework and rationale for adopting TRE to sustain gut health.
One of the important effects of gut–brain communication is to assess meal size and provide
information to the brain to modulate hunger and satiety. Mechanosensitive pathways that sense
gut distension independent of nutrient composition and chemical pathways that sense meal com-
position participate in this gut–brain communication. Mechanosensitive gastric vagal afferents
(GVAs) exhibit diurnal rhythmicity in their response to food-related stimuli, allowing for specific
time-of-day satiety signaling (55). When an obesogenic diet is given ad libitum to rodents, this
diurnal rhythmicity is ablated (56), which may enable animals to consume food at a non-preferred
time. Therefore, a loss of diurnal rhythm in the GVA axis can further accentuate hyperphagia and
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obesity. TRF of the same obesogenic diet has been reported to restore the daily rhythm of GVA
responsiveness to meal size (54). This result from studies in rats might explain the reduced hunger
at bedtime seen among human volunteers practicing TRE (44, 116).
The gut microbiome is presumed to play an important role in host metabolism and physiology.
Although it is generally accepted that having a diverse group of species in the gut microflora is
protective against obesity and metabolic diseases, there was no significant difference in overall
diversity or species richness between mice fed an obesogenic diet ad libitum or mice on TRF
(133). However, it cannot be ruled out that the gene expression pattern of these species is affected
by an ad libitum or TRF pattern, which might affect microbiome–host interaction, leading to
changes in luminal metabolite content.
Metabolomic analyses of fecal matter from ad libitum–fed and TRF mice showed significant
differences that may explain some of the improvements seen in the TRF mice. Hemicellulose
in the diet is typically broken down to xylose and galactose by the gut microbes, and some of
this is absorbed by the host. Relative to ad libitum–fed mice, TRF mice excreted significantly
more xylose and galactose in their stool, which implies that TRF reduced host absorption of these
simple sugars. The stool of TRF mice was also rich both in primary and secondary bile acids (133).
Usually, a significant portion of bile acids is reabsorbed from the gut. Elevated levels of bile acids
in the stool of TRF mice indicate that some of the reduction in hepatic and serum cholesterol in
TRF mice may be due to the net elimination of bile acids in stool.

TIME-RESTRICTED FEEDING AND BRAIN HEALTH

Most studies in rodents and humans have focused on body weight, body composition, and
metabolic health. Some preliminary results from animal experiments indicate that TRF may also
benefit brain health, specifically by protecting against or delaying the onset or development of neu-
rodegenerative diseases. Gene expression and phenotypic assessments of TRF and ad libitum–fed
flies and mice have shown several molecular signatures that support this notion: (a) TRF reduces
mitochondrial electron transport chain activity, thereby potentially reducing the levels of reactive
oxygen species in Drosophila heart (43); (b) TRF improves the structural integrity of the endoplas-
mic reticulum and mitochondria in Drosophila heart and mouse liver (43, 49); (c) TRF enhances
the integrative stress response by slightly reducing mTOR activation and increasing the unfolded
protein response in mouse liver (21); (d) in rodents, TRF improves motor coordination (21, 23,
49); and (e) Drosophila on TRF show sleep improvement (43) (Figure 3). If some of these results

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from non neuronal tissues extend to the nervous system, we should anticipate the alleviation of
disease severity in animal models of neurodegenerative diseases under TRF. Two recent studies
have demonstrated that mouse models of Huntington’s disease subject to TRF show improvement
in motor coordination, sleep, and autonomic nervous system function (126, 128). Also, gene ex-
pression markers of the disease in the striatum were normalized in TRF mice (126). These early
indications in animal models raise the hope that TRE in humans may delay the onset of neurode-
generative diseases or reduce the severity of these diseases.

PERSPECTIVE ON THE FUTURE OF TIME-RESTRICTED EATING

The demonstrated success of TRF in combating obesity and metabolic diseases in animals is rais-
ing substantial hope for its long-term potential in improving public health and reducing healthcare
costs. Although nutrition management is considered to be central to combat obesity and metabolic
diseases, the emphasis has so far been on caloric reduction and nutritional quality amelioration.
The effectiveness of these approaches for health improvement may be substantially increased if
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they are combined with optimal timing for meals. As rodent studies have indicated, if ingested at
the wrong circadian time, even reduced-calorie diets may not achieve their full potential in re-
ducing body weight (1). Similarly, human volunteers going through nutrition-based weight-loss
programs fail to achieve optimal weight loss if calories are consumed later in the circadian day (41).
Recently, the ketogenic diet has been considered to be effective in managing metabolic diseases,
including diabetes. However, as seen in a recent rodent study, a ketogenic diet given ad libitum
led to excessive weight gain, while a ketogenic diet combined with TRF improved several markers
of health and increased the healthy life span (87, 101). Altogether, these observations suggest that
traditional and emerging approaches for weight and disease management can benefit from being
combined with TRE.
Rigorous TRE without caloric reduction, as rodents were subject to, is difficult to implement in
large human cohorts. To our knowledge, only a few studies have been published that used TRE as a
health intervention (6, 40, 44, 53, 66, 82, 116, 121) (Table 1), yet many are ongoing. Nevertheless, a
controlled study on a small cohort has shown that TRE of 6 hours (versus 12 h) for 5 weeks did not
lead to weight loss, but it did increase β-cell function and insulin sensitivity and decreased post-
prandial insulin, oxidative stress, blood pressure, and appetite (116). This preliminary human study
lends support to the idea that TRE can improve human health even without a reduction in weight.
A few pilot feasibility studies have shown that time restriction is often accompanied by caloric
reduction (40, 44). In some of the pilot studies, CR was as much as 20% (44). Aiming for caloric
reduction without making an overt attempt at calorie counting is remarkable because the most
extensive and long-term caloric reduction study (CALERIE-2) achieved only 12% caloric reduc-
tion against a targeted reduction of 25% (28). In lieu of the practical outcome of TRE in reducing
caloric intake in many individuals, it is highly likely that long-term efficacy studies of TRE on
health outcomes will emerge from the contributions of CR, TRE, and circadian optimization.
The obvious first step in implementing TRE as a public health intervention will be to assess the
size of the populations that habitually spread caloric intake over a longer period of time or changes
sleep and eating patterns on the weekend. These populations will likely benefit from TRE. The
next step will be to assess whether long-term TRE is a sustainable modifiable behavior. Although
conventional thinking is that people usually eat three meals within a 12-h window every day (116),
studies using the objective measures of temporal patterns of caloric intake among those who do
not do shift work have found that only 10% of the adult population in a relatively small US cohort
consumed all caloric intake within 12 h or less, and 50% consumed calories during a period of 15 h
or longer (44). This eating pattern was also found among those in India who do not do shift work

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Table 1 Studies of time-restricted eating (TRE) interventions in humans

Duration of Time of eating Duration of Study Nutrition
Study eating window window TRE Participants design during TRE Result of TRE
NU39CH12_Panda

Hutchison 9h Early: 8:00 a.m. 7 days in N = 15 males; overweight; Crossover No data ↓ Body weight
et al. (53) to 5:00 p.m. each age 55 ± 3 years No change in body fat
Delayed: condition ↓ Glucose incremental area under the
12:00 p.m. to curve for a mixed-nutrient meal for
9:00 p.m. both early and delayed TRE
↓ Mean fasting glucose in early TRE

12.18
using a continuous glucose monitor
ARjats.cls

↓ Fasting triglycerides for both early

and delayed TRE
Gabel et al. 8h 10:00 a.m. to 12 weeks TRE group: n = 23 (20 females Matched No data ↓ Body weight
(40) 6:00 p.m. and 3 males); historical No change in body fat
BMI 35 ± 1; age 50 ± 2 years controls ↓ Energy intake

Chaix et al.
Control group: n = 23 ↓ Blood pressure
(21 females and 2 males);
BMI 34 ± 1; age 48 ± 2 years
May 29, 2019

Antoni et al. Varied: mean = Breakfast 10 weeks TRE group: n = 7 (6 female, Randomized No data No change in body weight

occur before final publication.)

(6) 517 min delayed and 1 male) controlled ↓ Body fat

June 10, 2019. (Changes may still

(8 h 37 min), dinner Control group: n = 6 (females) trial ↓ Energy intake

Review in Advance first posted on

SEM = advanced by Baseline BMI for both groups:
13:52

22 min 1.5 h each 20–39

Baseline age for both groups:
29–57 years
Sutton et al. 6 h or 12 h 8:00 a.m. to 5 weeks in N = 8 (males); overweight and Crossover 3 meals/day No change in body weight
(116) 2:00 p.m. or each prediabetic; age 56 ± 9 years provided Body fat not measured
8:00 a.m. to condition with matched ↑ Insulin sensitivity, β-cell function,
8:00 p.m. nutrients and fasting triglycerides
↓ Blood pressure, oxidative stress,
postprandial insulin, evening
appetite
Moro et al. 8h TRE group: 8 weeks TRE group: n = 17 (males); RT; Randomized 3 meals/day No change in body weight
(82) 1:00 p.m.to BMI = 29.94 ± 4.07 controlled with ↓ Body fat
9:00 p.m. or Control group: n = 17 (males); trial nutrients ↓ Testosterone and insulin-like growth
Control group: RT; BMI = 28.47 ± 3.48 matched to factor 1
8:00 a.m.to food journals Maintained muscle mass
9:00 p.m.
Tinsley et al. 4 h/4 days per 4 h between 8 weeks TRE and RT: n = 10 (males); Randomized No data No change in body weight or body fat
(121) week and 4:00 p.m. and age 22.9 ± 4.1 years controlled ↑ Upper and lower body strength and
then 12:00 a.m. on Unrestricted eating and RT: trial lower body muscular endurance
unrestricted non-workout n = 8 (males); age 22.0 ± ↓ Energy intake
days 2.4 years No adverse effects on lean mass
retention or muscular
improvements with short-term RT
Gill & Panda 10–12 h Decided by 16 weeks and N = 8 (5 males, 3 females); Within- No data ↓ Body weight
(44) participant 1 year BMI >25; and >14 h eating participant Body fat not measured
follow-up window at baseline; ↓ Hunger at night
age 24–30 years ↑ Morning and overall energy levels
and sleep satisfaction
LeCheminant 13 h 6:00 a.m. to 2 weeks N = 29 (males); healthy; Crossover No data ↓ Body weight
et al. (66) 7:00 p.m. age 20.9 ± 2.5 years Body fat not measured
↓ Energy intake

Abbreviations: BMI, body mass index; RT, resistance training.

 NU39CH12_Panda ARjats.cls May 29, 2019 13:52

(46)—that is, in a country experiencing a rapid increase in metabolic diseases. Research into sleep
habits among the general population in developed countries has also indicated that more than
75% of the adult population delays their wake-up time on the weekend, and they are also likely to
shift their breakfast time on the weekend. Altogether, it is safe to assume that a large fraction of
the population in both developing and developed countries would benefit from consistent TRE
lasting for a period of 10–12 h.
There are few studies on the efficacy and mechanisms of TRE in humans (Table 1). TRE
lasting for a period of 10 h was sustained for up to a year in a small cohort of eight adults. Al-
though the sample size is small, the feasibility of sustaining TRE for such a long period and the
accompanying weight loss of ∼3.85% among overweight (not obese) adults is encouraging (44).
Preliminary results from an obese cohort of 23 participants who lost a modest 2.6% of body
weight and achieved a 7-mm reduction in systolic blood pressure are also encouraging (40). Al-
though the study in the obese cohort targeted TRE to 8 h, participants were not closely monitored
for adherence, whereas the study in overweight adults targeting TRE lasting for 10 h (in which
participants achieved greater weight loss) was monitored through daily self-reporting using the
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Annu. Rev. Nutr. 2019.39. Downloaded from www.annualreviews.org

myCircadianClock app (https://mycircadianclock.org/). Therefore, it is important to monitor

time restriction both through self-reports and via sensors, such as continuous glucose monitors,
and this practice should be followed in future studies to objectively assess adherence to TRE and
health outcomes.
In summary, TRE has opened new avenues to assess the effects of the timing of eating on
metabolism, physiology, and behavior. Although animal experiments have produced great results
in preventing or reversing chronic metabolic diseases, the underlying mechanisms remain to be
explored. More rigorous human studies are also needed to assess the mechanisms and efficacy of
TRE in a wide range of diseases.

DISCLOSURE STATEMENT
S.P. is the author of The Circadian Code: Lose Weight, Supercharge Your Energy and Transform Your
Health from Morning to Midnight, for which he receives royalties. The authors are not aware of any
affiliations, memberships, funding, or financial holdings that might be perceived as affecting the
objectivity of this review.

ACKNOWLEDGMENTS
S.P. received funding from the US National Institutes of Health (grants EY016807, DK118278,
DK115214), Department of Defense (grant W81XWH1810645), and Department of Home-
land Security (grant EMW-2016-FP-00788), as well as the Robert Wood Johnson Foundation
(grant 76014), the Paul F. Glenn Center for the Biology of Aging, the Leona M. and Harry B.
Helmsley Charitable Trust (grant2012-PG-ME002), and the Brown Foundation. E.N.C.M. is
supported by a fellowship from the Larry L. Hillblom Foundation. A.C. received an American
Heart Association Career Development Award (grant 18CDA34110292) and has received support
from the Philippe Foundation; A.C. has also received a Women in Science Award from the Salk
Institute.

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