Pflügers Archiv - European Journal of Physiology

https://doi.org/10.1007/s00424-020-02381-6

INVITED REVIEW

Metabolic implications of circadian disruption

Narjis Fatima 1 & Sobia Rana 1

Received: 23 January 2020 / Revised: 16 April 2020 / Accepted: 17 April 2020

# Springer-Verlag GmbH Germany, part of Springer Nature 2020

Abstract
Circadian rhythms are generated by the circadian clock, a self-sustained internal timing system that exhibits 24-h rhythms in the
body. In mammals, circadian rhythms are driven by a central clock located in suprachiasmatic nucleus and various peripheral
clocks located in different tissues and organs of the body. Many cellular, behavioral, and physiological processes are regulated by
the circadian clock in coordination with environmental cues. The process of metabolism is also under circadian regulation. Loss
of synchronization between the internal clock and environmental zeitgebers results in disruption of the circadian rhythms that
seriously impacts metabolic homeostasis leading to changed eating behavior, altered glucose and lipid metabolism, and weight
gain. This in turn augments the risk of having various cardio-metabolic disorders such as obesity, diabetes, metabolic syndrome,
and cardiovascular disease. This review sheds light on circadian rhythms and their role in metabolism with the identification of
gaps in the current knowledge that remain to be explored in these fields. In this review, the molecular mechanisms underlying
circadian rhythms have been elaborated first. Then, the focus has been kept on explaining the physiological significance of
circadian rhythms in regulating metabolism. Finally, the implications for metabolism when these rhythms are disrupted due to
genetic mutations or social and occupational needs enforced by modern lifestyle have been discussed.

Keywords Circadian rhythms . Metabolism . Clock genes . Shift-work . Gut microbiota . Metabolic disorders

Introduction cellular, biochemical, physiological, and behavioral processes

Since the dawn of life, organisms have undergone evolutionary
adaptation as a response to daily environmental cycles resulting
from Earth’s rotation about its axis, in particular diurnal varia-
tions in sunlight and temperature [26]. Many biological func-
tions such as cellular, physiological, and behavioral processes
exhibit rhythmic fluctuations that follow a 24-h cycle. For in-
stance, a rise in heart rate, blood pressure, and body temperature
is seen in the morning, while a decrease in these parameters is
observed in the evening. These variations in biological activi-
ties are referred as circadian rhythms and are generated by an
endogenous timing system, the circadian clock that produces
about 24-h rhythms [107]. In organisms as diverse as bacteria
and mammals, the circadian clock aligns the oscillations in
Narjis Fatima and Sobia Rana contributed equally to this work.
* Sobia Rana
molecularbiologist1@gmail.com; sobia.rana@iccs.edu
1
Molecular Biology and Human Genetics Laboratory, Dr. Panjwani
Center for Molecular Medicine and Drug Research (PCMD),
International Center for Chemical and Biological Sciences (ICCBS),
University of Karachi, Karachi 75270, Pakistan
with changing solar cycles throughout the seasons. The envi-
ronmental cues that synchronize the body’s internal clock with
the external environment are known as zeitgebers (time givers)
[41, 62, 66, 108]. The activities regulated by circadian rhythms
include sleep-wake cycle, body temperature, blood pressure,
secretion of hormones, and metabolism [117, 132]. Taking into
account the complex relationship between the circadian clock
and metabolism, it is perhaps not surprising that disturbed cir-
cadian rhythms that influence the normal metabolic pathways
and may lead to various cardio-metabolic disorders including
obesity, diabetes, metabolic syndrome, and cardiovascular dis-
ease. Similarly, as a consequence of altered sleep-wake cycle,
disrupted circadian rhythms may have a considerable impact on
behavior and work activities [133]. Recent studies have shown
that in mammals, around 80% of protein-coding genes present
in various tissues and organs show circadian oscillations at
transcriptional level. For example, in baboons, 82% of genes
involved in cellular metabolism and other biochemical func-
tions are expressed in a circadian manner in at least one tissue
[96]. In mice, 43% of protein-coding genes show rhythmicity in
their expression [145]. In this review, wewill discuss the mo-
lecular mechanism underlying the regulation of circadian clock
system. Moreover, we will review the role of clock genes in

regulating metabolism. Afterward, we will discuss how some
behaviors or lifestyles cause misalignment of the circadian
clock.
Central and peripheral clocks
Circadian rhythms in mammals are regulated by a central
clock and various peripheral oscillators (Fig. 1). Central clock
is located in suprachiasmatic nucleus (SCN) of anterior hypo-
thalamus, while peripheral clocks exist in different tissues and
organs of the body including brain, liver, adipose tissue, and
muscles [9, 108]. Surgical removal of SCN in rats was found
to abolish the circadian rhythms in peripheral organs
Fig. 1 Central and peripheral clocks in human. Suprachiasmatic nucleus
(SCN) receives light signals from the external environment through
retinohypothalamic tract and entrains the central clock to a 24-h cycle.
Central clock synchronizes the peripheral clocks by humoral and neuro-
nal signals and regulates various physiological processes in peripheral
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signifying its role as a central pacemaker or master clock in
synchronizing the various self-sustained clocks present in the
peripheral organs [112]. SCN receives light from the external
environment through the retinohypothalamic tract that en-
trains the central clock to a 24-h cycle [43]. The central clock,
in turn, synchronizes the peripheral clocks and regulates phys-
iological processes and behavior in a circadian manner [6].
Although circadian rhythms in the central clock are mainly
coupled with light-dark cycle, the most important zeitgeber
in peripheral organs such as liver, pancreas, and heart is food.
Restricted feeding in mice was observed to alter rhythmic
gene expression in peripheral clocks without affecting the
central clock and to uncouple the peripheral clocks from the
central one [6, 33].
tissues and organs (liver, adipose tissue, muscles, pancreas, heart, etc.)
in a circadian manner. Light-dark cycle is important zeitgeber for the
central clock, while food is the most dominant cue for the peripheral
clocks
Pflugers Arch - Eur J Physiol
Circadian clock at molecular level
At molecular level, the circadian system is regulated by tran-
scriptional and translational feedback loops of circadian clock
genes (Fig. 2). Core circadian clock genes include Clock,
Bmal1, Per (Per1 and Per2), and Cry (Cry1 and Cry2) genes.
Both Clock and Bmal1 genes act as positive regulators, and
their protein products dimerize to form a CLOCK-BMAL1
complex that initiates transcription of Per and Cry genes.
After reaching a significant concentration, protein products
of Per and Cry genes act as negative regulators and inhibit
transcription of positive regulators [108, 126]. An additional
negative feedback loop consisting of Rev-erbα and RORα
genes is also involved in the regulation of circadian rhythms.
CLOCK-BMAL1 heterodimer initiates the transcription of
Rev-erbα and RORα genes whereas protein products of Cry
and Per genes inhibit this transcription in a circadian manner
[106]. REV-ERBα and RORα compete for the Bmal1 gene
binding element RORE (retinoic acid-related orphan receptor
Fig. 2 Molecular framework of circadian clock. BMAL1-CLOCK het-
erodimer binds to E-Boxes in promoter regions and regulates expression
of Cry1/2, Per1/2, Rev-erbα, RORα, and various clock-controlled genes.
The protein products of Cry1/2 and Per1/2 genes act as negative regula-
tors. When CRY1/2 and PER1/2 proteins reach a particular concentration
in cytoplasm, they form a heterodimer, which translocates to the nucleus
and interacts with the BMAL1-CLOCK and inhibits their transcription.
REV-ERBα acts as a negative regulator and inhibits Bmal1 transcription
whereas RORα acts as a positive regulator and initiates the transcription
response element) that is present in the promoter region of
Bmal1. REV-ERBα binds to the promoter region of the
Bmal1 gene and acts as a negative regulator for inhibiting its
transcription. On the other end, RORα protein initiates the
transcription of Bmal1 [53]. This additional feedback loop
(REV-ERBα and RORα) links both negative (PER and
CRY) and positive (BMAL1 and CLOCK) feedback loops.
In addition to core clock genes, the circadian system also
involves clock-controlled genes. The products of core clock
genes act as transcriptional factors for directly or indirectly
regulating the expression of clock-controlled genes [107],
while clock-controlled genes are involved in the regulation
of various biological processes including metabolism [97]. A
recent study involving Rev-erbα/β double-knockout mouse
embryonic stem cells revealed that REV-ERBα/β has a sig-
nificant role in the regulation of mammalian circadian clock
via controlling the expression of various clock-controlled
genes [64]. Therefore, disruption of core clock genes may
alter the expression of genes involved in various physiological
of the Bmal1 gene by binding on the RORE site in the promoter region of
Bmal1. PPARα binds to Bmal1 gene and regulates its transcription.
BMAL1, brain and muscle ARNT-like 1; CRY1/2, cryptochrome1/2;
PER1/2, period1/2; REV-ERBs and RORs, retinoic acid related orphan
nuclear receptors; RORE, retinoic acid-related orphan nuclear receptor
response elements; PPARα, peroxisome proliferator-activated receptor
alpha; PPRE, peroxisome proliferator response element; DBP, D-site
binding protein

processes such as metabolic activities suggesting a significant
role of the circadian clock in regulation of key metabolic
genes [86].
Role of circadian clock in regulating
metabolism
The circadian clock regulates metabolism in mammals by
interacting with multiple physiological, genetic, and envi-
ronmental factors. Clock genes generate daily rhythms of
sleep/wake cycle, feeding-fasting cycle, and metabolism in
response to exogenous factors [90]. Circadian system reg-
ulates several metabolic processes including glucose and
cholesterol metabolism [57]. Regulation of other physio-
logical functions such as blood pressure and heart rate is
also carried out in a circadian manner [25]. In addition,
plasma levels of hormones involved in metabolic processes
such as glucagon and leptin display circadian oscillations
[69, 110]. Similarly, glucose transporters and glucagon re-
ceptors exhibit circadian rhythms [17]. Any disturbance in
the interaction of the circadian system with environmental
factors has been shown to have harmful effects on metab-
olism, physiology, and behavioral processes of the organ-
ism. Besides, mutations in circadian clock genes may lead
to various metabolic disorders [90]. Genes involved in the
metabolism of nutrients are expressed rhythmically. For
instance, genes encoding enzymes involved in the regula-
tion of glucose and cholesterol metabolism show rhythmic
expression [44]. Nuclear receptor genes involved in the
regulation of metabolism such as PPARs, Rev-Erbs, and
RORs have also been found to display circadian oscilla-
tions in their expression [22, 73]. Both Rev-Erbs and
RORs connect the circadian clock with the metabolic pro-
cesses [37, 36]. REV-ERBα/β regulates lipid metabolism
in the liver. Declined levels of REV-ERBα/β lower the
expression of several genes involved in metabolism and
cause hepatic steatosis [15]. Likewise, PPAR genes are in-
volved in energy homeostasis and regulation of lipid me-
tabolism. PPARα is an important link between circadian
clock and metabolism [24]. It plays an important role in
the regulation of circadian rhythms and is involved in the
regulation of lipid and protein metabolism [116].
Moreover, it also activates metabolic pathways in response
to starvation such as ketogenesis and hepatic fatty acid
oxidation [78]. PPARα expression is regulated by the
CLOCK-BMAL1 heterodimer protein complex. PPARα,
in turn, binds to the Bmal1 gene and regulates its transcrip-
tion [116]. Bmal1 knockout and Clock mutant mice have
been observed to have diminished expression of PPARα in
the liver as compared with wild-type mice [18, 98]. PPARγ
gene is involved in adipogenesis and lipogenesis in adi-
pose tissues [82]. Deletion of PPARγ gene in mice led to
Pflugers Arch - Eur J Physiol
loss of diurnal variations in food intake and other metabol-
ic parameters such as blood pressure, heart rate, and heat
production [142]. PPARδ connects the circadian clock with
diurnal variations in body temperature [140]. Similarly,
Sirtuin genes are also involved in the regulation of clock-
controlled genes by controlling gene expression of core
clock genes Bmal1 and Clock [80]. Sirt1, Sirt3, and Sirt6
genes have a significant role in the regulation of circadian
clock, and these genes also link circadian clock with met-
abolic homeostasis [88]. Sirt1 gene regulates metabolic
processes such as glucose and lipid metabolism, insulin
secretion, and fatty acid oxidation in mitochondria [147].
Sirt3 gene expression was found to be reduced up to 50%
in the mouse model of diabetes whereas calorie restriction
led to increased expression of Sirt3 [67]. A high-fat diet in
mice disturbed the expression of clock genes in different
tissues by suppressing SIRT1 protein [122].
Circadian disruption and metabolic anomalies
Disruption of circadian rhythms as a consequence of itera-
tive alterations in lifestyle may affect well-being and normal
physiological processes in humans (Fig. 3). Disrupted cir-
cadian rhythms represent a well-known risk factor for pro-
moting various cardio-metabolic disorders like metabolic
syndrome, diabetes, and cardiovascular disease [84].
Metabolic syndrome is the presence of at least three or more
of the five metabolic anomalies such as central obesity, hy-
perglycemia, insulin resistance, dyslipidemia, and hyper-
tension [61]. Metabolic syndrome increases the rate of mor-
tality worldwide as it leads to development of diabetes and
cardiovascular diseases [137]. Diabetes is a major metabolic
disorder estimated to cause 380 million deaths worldwide
by 2025 [42]. Majority of deaths in diabetic patients are due
to cardiovascular diseases [39]. Circadian misalignment
(shift work and eating at night) led to increased arterial
blood pressure, reduced plasma levels of leptin, increased
glucose and insulin levels, and a significant reduction in
sleeping efficiency in humans [77, 114]. There is a great
variability in the way humans manage their sleep and wake-
fulness during the 24-h day. Many studies have reported a
strong association of evening-chronotype (the tendency of a
person to wake up late and sleep late) with the metabolic
disease [144]. Moreover, a recent study has reported that
morning persons are mentally healthy as compared with
evening persons, but no evidence is found for the causal link
of chronotype with the risk of being diabetic or obese [68].
Further studies are required to explore whether metabolic
disorders are more significantly correlated with misalign-
ment of circadian rhythms as a result of shift work or eating
at night as compared with the chronotype of individuals.
Pflugers Arch - Eur J Physiol
Fig. 3 Implications of iterative alterations of life style and mutations of
circadian clock genes for metabolic health. Disturbances in interaction of
the circadian system with environmental factors disrupt the circadian
clock. These circadian misalignments such as eating at night, exposure
to artificial light at night, night shift work, and mutations in circadian
Clock genes’ mutants and metabolism
The disruption of circadian rhythms owing to either complete
ablation or mutations of clock genes in animal models has
provided evidence for the association of circadian rhythms
with risk of developing various metabolic disorders (Fig. 1,
Table 1). The circadian clock mutant mice were observed to
develop metabolic anomalies such as hyperphagia, obesity,
hyperglycemia, hyperlipidemia, hyperleptinemia, and
hypoinsulinemia with accumulation of fats in the liver [44,
104, 131]. In Bmal1 knockout mice, increased levels of circu-
lating triglycerides, cholesterol, and free fatty acids resulted in
deposition of fat in organs other than adipose tissues including
the liver and muscles [118]. An accumulating amount of stud-
ies has shown that disruption of clock genes has a significant
role in the development of diabetes. For instance, Bmal1 de-
ficient mice have been found to exhibit altered glucose me-
tabolism and impaired insulin signaling leading to develop-
ment of insulin resistance and obese phenotype [120]. In ad-
dition, Clock and Bmal1 mutant mice were found to have
impaired insulin secretion leading to the development of dia-
betes [85]. Similarly, Per2 knockout mice have been observed
to have aberrant blood insulin levels due to its reduced clear-
ance as compared with wild-type mice [146]. In addition, Cry
clock genes have harmful effects on metabolism. Disrupted circadian
system causes various cardio-metabolic anomalies such as obesity, dia-
betes, and cardiovascular disease. HDL-C, high density lipoprotein
cholesterol
gene mutation in mice was reported to result in the develop-
ment of diabetes [99]. Moreover, mutations in mice’s core
clock genes were observed to alter the expression of key genes
involved in regulation of liver’s glucose and lipid metabolism
[74, 75]. It was shown in mice that pancreas specific Bmal1
gene expression is necessary for glucose metabolism, and its
deletion can lead to altered insulin secretion [111]. Likewise,
liver-specific deletion of Bmal1 in mice was shown to result in
hypoglycemia during the fasting phase, altered circadian ex-
pression of some liver genes involved in glucose metabolism
and impaired clearance of circulating glucose, thus, suggest-
ing a role of Bmal1 in the regulation of circadian homeostasis
of glucose [75]. Moreover, skeletal muscle-specific Bmal1
deletion in mice led to reduced glucose uptake and decreased
expression of glucose transporter GLUT4. Besides, the activ-
ity of key enzymes involved in glycolysis in skeletal muscles
was also found to be diminished and led to impaired glucose
metabolism in muscle tissues. Systematic homeostasis of glu-
cose was also disturbed in these mice [56]. Likewise, Bmal1
gene in mice adipose tissue was shown to be involved in lipid
metabolism and regulation of body temperature, fatty acid
oxidation, and energy homeostasis [19]. These pieces of evi-
dence suggest that peripheral clocks play a significant role in
the regulation of glucose. Furthermore, both Clock mutant and
 Pflugers Arch - Eur J Physiol

Table 1 Metabolic implications reported for circadian clock genes’ knockout/mutant organisms

Knockout/mutation Tissue-specific/whole body Phenotype Ref.

Bmal1−/− Liver-specific Elevated serum triglycerides (TGs), increased hepatic lipid, [21, 75]
and impaired clearance of circulating glucose
Bmal1−/− Whole-body Increased levels of free fatty acids, TGs, and [118]
cholesterol. Deposition of fat in adipose tissues,
liver, and muscles
Bmal1−/− Whole-body Glucose intolerance and reduced insulin secretion [120]
leading to insulin resistance and obesity
Bmal1−/− Whole-body Glucose intolerance, reduced insulin secretion, [85]
defective size, and multiplication of pancreatic islets
Bmal1−/− Smooth muscle-specific Disturbed rhythms of blood pressure [139]
Bmal1−/− Whole-body Elevated cholesterol and triglycerides, impaired [2]
vascular remodeling, vascular injury, and
endothelial dysfunction
Bmal1−/− Whole-body Disturbed rhythms of blood pressure and heart rate [31]
Bmal1−/− Adipose tissue-specific Altered feeding behavior and obese phenotype [104]
Bmal1−/− Pancreas specific Altered secretion of insulin [111]
Bmal1−/− Skeletal muscle-specific Impaired glucose metabolism in muscles and disturbed [56]
homeostasis of glucose in the whole body
Clock−/− Whole-body Slight weight gain [35]
Clock mutant Whole-body Glucose intolerance, delayed insulin signaling, defective [85]
size, and multiplication of pancreatic islets
Clock mutant Whole-body Vascular injury, thrombosis, and endothelial dysfunction [2]
Clock mutant Whole-body Disturbed circadian rhythms of blood pressure and heart rate [31]
Cry1−/−, Cry2−/− Whole-body Circadian variation in heart rate [89]
Cry1−/−, Cry2−/− Whole-body Weight gain and impaired glucose metabolism [21]
Cry1−/−, Cry2−/− Whole-body High-fat diet-induced obesity and hyperinsulinemia. [11]
Increased fatty acids storage in adipose tissues
Cry1 mutant Whole-body Diabetes [99]
Per2−/−/, Cry1−/− Whole-body Decreased energy metabolism [58]
Per2−/− Whole-body Circadian variation in feeding behaviorProne to obesity [141]
Per2−/− Whole-body Altered lipid profile, reduced levels of triacylglycerol, [51]
and increased adipocyte differentiation
Per2−/− Whole-body Reduced clearance of insulin [146]
Per1,2,3−/− Whole-body Prone to obesity [32]
PPARγ−/− Whole-body Circadian variation in food intake, blood pressure, heart [142]
rate, and heat production
Rev-erbα/β−/− Liver-specific Hepatic steatosis and dyslipidemia [21]

Bmal1 knockout mice were found to develop pathological
vascular remodeling and endothelial dysfunction in response
to vascular injury [2]. Also, smooth muscle Bmal1 deletion in
mice dampened the amplitude of blood pressure circadian
rhythm and decreased blood pressure. Similarly, altered circa-
dian rhythms for blood pressure and heart rate were also seen
in Bmal1 knockout, Cry1 and Cry2 knockout, and Clock mu-
tant mice [31, 89]. However, further mechanistic studies are
needed to better comprehend the clock genes’ role in periph-
eral organs along with the molecular pathways and pathogenic
mechanism of cardiovascular disorders related to circadian
disruption of blood pressure. [30, 130, 139]. The products of
core clock genes Per2 and Cry1 were reported to control the
expression of genes involved in the regulation of energy me-
tabolism in zebrafish [58]. Also, the Cry gene knockout mice
were seen to be more susceptible to diet-induced obesity as
compared with wild-type mice. Additionally, increased secre-
tion of insulin and increased fatty acid storage in adipose
tissues were also observed in these mice [11]. Likewise,
Clock deficient mice showed slight weight gain as compared
with wild-type mice, but results were not statistically signifi-
cant [35]. PER2 controls lipid metabolism and adipogenesis
by regulating the expression of PPARγ and PPARγ-target
genes. Mice lacking Per2 gene had variation in feeding be-
havior and developed obesity. Altered lipid profile and severe
reduction of triacylglycerol levels were observed in Per2
knockout mice. Furthermore, fibroblasts of Per2 knockout
mice were found to have enhanced adipocyte differentiation
[51, 141]. Adipose tissue-specific Bmal1 knockout mice were
found to have altered feeding behavior and obesity [104]. In
Pflugers Arch - Eur J Physiol
the same way, Per1,2,3 knockout mice were found more
prone to obesity as compared with wild-type mice suggesting
a significant role of Per genes in the regulation of body weight
[32]. In a similar manner, the Clock gene polymorphisms in
humans were found to be associated with metabolic syndrome
[115]. Additionally, expression levels of circadian clock genes
in humans were also observed to be negatively associated with
parameters of metabolic syndrome. For instance, expression
of Per2 in visceral adipose tissues was inversely associated
with waist circumference. Likewise, significant inverse asso-
ciation of Bmal1, Cry, and Per2 gene expression levels with
total and low-density lipoprotein cholesterol was observed
[49]. However, more studies are warranted to investigate the
tissue-specific role of circadian clock genes in lipid and glu-
cose metabolism.
Metabolic status of rodent models of night
shift work
Rodent models that mimic the night shift work schedule in
humans are being used to better understand the system behind
the synchronization of circadian clock with the geophysical
time [38]. Rodent model of shift work (male Wistar rats) were
subjected to feeding and forced activity during their normal
sleep period. These rats exhibited a loss of synchronization
between SCN and liver. Moreover, expression levels of core
clock genes (Per1, Clock, and Bmal1) were altered, and the
expression of Per2 lost rhythmicity in the liver. Furthermore,
clock-controlled genes involved in the regulation of metabolic
processes lost synchronization with circadian clock genes in
rat liver [113]. Mice exposed to a 20-h light-dark cycle, which
was incompatible with their internal circadian clock, were
found to have disrupted circadian clock. These conditions
resulted in negative effects on physiology including increased
levels of insulin and leptin, altered body temperature, weight
gain, and obesity [70]. In another mouse model of shift work,
early pathophysiological effects of shift work on molecular
circadian machinery were observed. Circadian expression of
core clock genes and clock-controlled genes was found to be
severely disrupted in the liver, while Bmal1, Per1, Dbp, and
Rev-erbα genes’ expression was disrupted moderately in
SCN. These early pathophysiological effects of shift work
may precede metabolic disorders. When these mice were sub-
jected to time-restricted feeding, improvement in disrupted
glucose and lipid metabolism was observed suggesting that
minimizing food intake during the night in shift workers can
reduce the risk of metabolic disorders [10]. Poor sleep quality
along with having a high-fat diet led to impaired glucose tol-
erance in mice, while sleep recovery reversed the altered glu-
cose metabolism in mice exposed to a high-fat diet [59].
Studies exploring metabolic disorders in shift workers using
rodents as a model of shift work have highlighted great
importance of rodent models for future mechanistic studies
on shift work-related metabolic disorders. On the other hand,
conditions of shift work in humans are variable and not well-
defined. Therefore, it is difficult to design ideal animal
models; thus, there is a need for developing a standard animal
model having appropriate characteristics of shift work for fu-
ture research [52, 100].
Impact of shift work on human metabolic
health
Disruption of circadian rhythms due to shift work is associated
with obesity, diabetes, metabolic syndrome, and cardiovascu-
lar illnesses [3, 4, 34]. The circadian clock is disrupted by
insufficient sleep and leads to arrhythmic physiological pro-
cesses, altered glucose metabolism, and overweight/obesity in
humans [12, 92]. Altered sleep-wake cycle as a consequence
of night shift work is associated with disruption of the internal
clock that leads to altered metabolic homeostasis [121].
Synthesis of melatonin occurs during the darkness that results
in increased sleep tendency in humans [105]. Shift work and
exposure to artificial lights at night resulted in an altered syn-
thesis of melatonin [16, 50]. Reduced levels of melatonin in
humans give rise to disturbed sleep-wake cycle, decreased
insulin sensitivity, and glucose intolerance, eventually leading
to obesity [28]. Shift workers working at night and sleeping at
day time were found to have reduced energy expenditure
resulting in weight gain and obesity [93]. Glucose intolerance
in shift workers as a consequence of disrupted circadian
rhythms increases the risk of diabetes [95]. Night shift work
has also been found to be associated with increased levels of
cholesterol and triglycerides, low levels of HDL cholesterol,
increased BMI (body mass index; a measure of obesity), and
increased blood pressure ultimately leading to cardiovascular
diseases [14, 34, 54, 71]. Shift workers have been observed to
be more prone to the development of abdominal obesity [123].
Years of shift work exposure and age of workers were found to
be positively associated with an increase in BMI in individuals
working at night-shift. However, in individuals working dur-
ing the day-shift, the age of workers was found to be positive-
ly associated with the increase in BMI, but years of work
exposure were not associated with an increase in BMI [102].
Shift workers were reported to have higher risk of having
obese phenotype and poor health [8, 65, 72, 83, 138].
According to a study, energy intake between night and day
workers were similar suggesting that increasing rates of obe-
sity in shift workers were associated with circadian misalign-
ment caused by the timing of food intake and variation in
metabolism at night. However, it remained uncertain whether
this redistribution of food and alteration in food preference at
night is associated with the higher risk of obesity seen in the
shift workers [13]. A study reports that shift workers have

17% and 27% higher risk of developing obese phenotype and
diabetes, respectively. Additionally, association of shift work
with an increased risk of having cardiovascular diseases has
also been reported [125]. Another study reports the impact of
disturbed sleep-wake cycle and fasting-feeding cycle on cir-
culating metabolites in human subjects under controlled con-
ditions. In this study, many metabolites lost or reversed their
rhythmicity during simulated shift work. In addition, a great
majority of metabolites linked to nutrient metabolism
uncoupled their rhythmicity with SCN and were synchronized
with sleep-wake and eating schedule during shift work. [119].
However, the mechanism underlying circadian misalignment
with the external environment and to which extent dysregula-
tion of peripheral clocks is related to irregular working sched-
ule is still unknown. Prospective cohort studies on large scale
are still needed to know the consequences of shift work and its
association with obesity and other metabolic disorders.
Effect of exposure to light at night
on metabolic well-being
It is well-established fact that light can regulate circadian
clock that is involved in the regulation of metabolic pathways.
Exposure to artificial lights at night is suggested to cause
disruption of circadian rhythms in humans, which in turn leads
to deregulation of metabolic homeostasis and eventually met-
abolic disorders like overweight and obesity [44, 91]. Mice
exposed to constant 24-h bright light displayed glucose intol-
erance and weight gain without increasing the calorie intake as
compared with mice exposed to normal light-dark cycle [45].
Mice in response to 24-h continuous light exposure were ob-
served to have increased food intake and decreased energy
expenditure. Weight gain was also more rapid in mice exposed
to constant light as compared with mice having a high-fat diet.
Thus, indicating the role of constant light exposure in circadi-
an dysregulation of metabolism leading to insulin resistance
and obesity [29]. Mice exposed to constant dim light at night
developed altered food timings, increased white adipose tissue
mass, gained more body weight, and developed glucose intol-
erance as compared with mice exposed to normal light-dark
cycle. However, when these mice were kept back in a normal
light-dark cycle, the glucose clearance ability of mice was
recovered, and their food intake timings were also improved
[47]. Similarly, male mice fed a high-fat diet and exposed to
constant dim light at night exhibited exaggerated weight gain
as compared with mice exposed to normal light-dark cycle
and fed a normal diet. In addition, impaired glucose metabo-
lism, abnormal insulin secretion, altered feeding timing, and
peripheral inflammation were also observed in mice having a
high-fat diet and exposed to constant dim light at night [46]. In
mammals, SCN receives light through the retinohypothalamic
tract and synchronizes the peripheral clocks, but according to
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recent studies, light can also synchronize the peripheral clocks
in SCN-independent manner [63]. Zebrafish cell lines and
embryos have also been reported as light-responsive, and light
can directly entrain the circadian clock in these cell lines. [58,
127, 128]. Nevertheless, further research is still required to
fully elucidate the underlying mechanism by which the central
circadian clock synchronizes the peripheral clocks in light-
dependent manner.
Implications of irregular food timings
on metabolism
The role of eating habits in regulation of circadian rhythm’s
period has been indicated in several studies [5, 84]. Food is
one of the important zeitgebers that synchronizes the circadian
clock [44]. Irregular timings of food intake in humans may
lead to disruption of metabolic homeostasis [90]. Feeding pat-
terns in mice were found to be coordinated mainly by SCN
that regulate secretion of feeding-related hormones in a circa-
dian manner including ghrelin and leptin [69]. Leptin levels
were found low in individuals eating at night time that might
contribute to increased intake of food at night [94]. However,
some studies showed that leptin levels were similar between
individuals eating at night (consuming about half of the food
after the evening meal and awoke at night three times per
week for taking food) and healthy controls (consuming less
than a quarter of food after dinner and did not wake at night for
taking food) [1, 55]. Disrupted circadian rhythms in
Drosophila (fruit fly) were reported to result in muscle dys-
function and obesity. On the other hand, metabolic glitches
related to obesity were improved when the diet was restricted
in both clock mutant and wild type obese flies [134]. In circa-
dian clock mutant mice (whole-body Cry1, Cry2, and in liver-
specific Bmal1 and Rev-erbα/β knockout mice), time-
restricted feeding (TRF) prevented obesity and obesity-
related metabolic problems such as glucose intolerance, fatty
liver disease, and dyslipidemia as compared with clock mutant
mice that developed obesity and related metabolic disorders as
a consequence of free-feeding [21]. TRF was found to reduce
metabolic diseases (hepatic steatosis and hypercholesterol-
emia) arising as a result of various high-fat diets in mice.
Also, TRF was observed to reverse the development of met-
abolic disorders in mice with pre-existing obesity and type II
diabetes [20]. Moreover, TRF in mice resulted in rapid weight
loss, restoration of glucose tolerance, and decreased severity
of hepatic steatosis. Besides, mice subjected to TRF were
physically more active as compared with mice having free-
feeding [27]. On the other hand, when juvenile mice having
TRF in childhood period were subjected to free feeding in
adulthood, they were found to have severe irreparable dam-
ages including metabolic disorders, increased body weight,
immune system suppression, delayed sexual maturity, and
Pflugers Arch - Eur J Physiol
increased risk of cardiovascular diseases [60]. Early TRF (eat-
ing early in the day) in humans was observed to increase
insulin sensitivity and improve β cell function, and to decrease
blood pressure and oxidative stress [124]. Furthermore, TRF
in humans was witnessed to decrease the body weight, lower
the circulating levels of glucose, triglycerides, and low-
density lipoprotein cholesterol, and to increase the circulating
levels of high-density lipoprotein cholesterol [109]. However,
the mechanistic link between feeding patterns and metabolism
are yet to be explored. According to a recent study, eating at
night was found to be associated with metabolic syndrome in
women and dyslipidemia in both men and women [143].
Abnormal food timings can disrupt the circadian clock partic-
ularly high-calorie diet at night that may lead to metabolic
disorders like obesity. Individuals having a high-calorie diet
in breakfast easily lost their weight and had improved insulin
sensitivity as compared with individuals having a high-calorie
diet in dinner [48]. Temporal restriction of food intake in mice
can alter the phase of rhythmic expression of clock genes
(Per1, Per2, Per3, and Cry1) and clock-controlled genes
(Rev-erbα, Dbp, and Cyp2a5) in peripheral organs without
affecting the phase of rhythmic expression of clock genes
and clock-controlled genes in SCN, thus, uncoupling the pe-
ripheral clocks from SCN. Unexpected large changes in food
intake timings can reset the expression of genes that are
expressed in a circadian manner especially in the liver [33].
Nevertheless, further studies are warranted to estimate the role
of meal timing in diurnal secretion of hormones.
Circadian rhythms, gut microbiota,
and metabolism
Gut microbiota and circadian clock have an interrelated regu-
latory relationship that plays an important role in metabolic
health [101]. A growing body of evidence demonstrates that
gut microbiota (the microorganisms inhabiting the intestine)
play a significant role in the development of insulin resistance,
obesity, and metabolic syndrome [23]. Gut microbiota ex-
hibits diurnal oscillations in both microbial community com-
position and their metabolic activities. These changes in mi-
crobial rhythms are regulated by the time of eating and the
type of diet of the host. Circadian rhythms of host organism
can alter the composition and activity of the gut microbiota,
while gut microbiota can affect the host metabolism [135].
Many studies have suggested that gut microbiota may affect
the rhythmic expression of the biological clock of the host
[103]. Similarly, mutations in host circadian clock genes also
influence the circadian rhythms of gut microbiota. Per1/2
knockout mice exhibited a near-complete loss of diurnal os-
cillations in the composition and function of commensal bac-
teria in the intestine [129, 136]. Likewise, Bmal1 knockout
mice showed abolished rhythmicity in composition and
abundance of fecal microbiota [81]. Moreover, germ-free
(GF) mice displayed completely different central and hepatic
circadian clock with altered metabolic pathways. In addition,
the lack of gut microbiota in GF and antibiotic-induced mice
deregulated the expression of the clock genes (Bmal1, Per1,
Per2, and Cry1) in the liver and intestinal epithelial cells [79].
Gut microbes can alter host energy balance, metabolic pro-
gramming, and microbial metabolites. Expression levels of
key genes involved in the absorption of nutrients and metab-
olism in germ-free mice and specific pathogen-free mice were
altered in peripheral tissues especially in the intestine when
these mice were conventionalized with fecal microbiota [40,
76]. Several studies have reported a clear association of met-
abolic syndrome and obesity with disruption of microbiota
rhythm. Metabolites produced by gut microbiota are impor-
tant mediators that link gut microbiota with the host clock.
Thus, disturbance of this circadian network may lead to diet-
induced obesity [79, 135]. GF mice were found to have re-
duced adiposity, improved glucose tolerance, and insulin sen-
sitivity as compared with specific pathogen-free mice.
Moreover, GF mice were resistant to diet-induced obesity
[7]. Impaired absorption and metabolism of lipids in the small
intestine of germ-free mice implied that gut microbiota has an
important role in the metabolism and absorption of lipids and
can influence host circadian clock. Furthermore, GF mice
were partially protected from high fat diet-induced obesity
due to decreased dietary lipid digestion and absorption [87].
Gut microbes and circadian rhythms are linked via regulation
of metabolism, but the mechanisms underlying these interac-
tions are not well understood. Mechanistic studies are warrant-
ed to dissect the molecular mechanism underlying the corre-
lation of gut microbiota with the metabolism of the host.
Conclusion
Organisms have evolved and adapted their biological clock to
synchronize with the cyclic nature of the environment such as
light/dark cycle, availability of food, and changes in tempera-
ture. Body’s endogenous clock produces 24-h rhythms in the
body. The body’s clock is significantly affected by iterative
alterations of life style that causes misalignment of internal
clock with geophysical time. As circadian clock synchronizes
behavioral and physiological processes in the body with envi-
ronmental cues, any disturbance in synchronization of the
circadian system with the external environment is found to
have negative consequences and adverse effects on physiolo-
gy and metabolic processes. Disruption of the clock due to
shift work or modern lifestyles such as inappropriate timing
of food intake or disturbance in the sleep-wake cycle has
harmful effects on health and may lead to metabolic syn-
drome, obesity, diabetes, and cardiovascular diseases. At pres-
ent, research on chronobiology (the study of biological

rhythms) is becoming significant and constantly growing in
fields of biology and medicine. Even though the mechanism
of circadian clock disruption in knockout or mutant animal
models does not replicate the conditions of human physiology
and metabolism but it provides some understanding of meta-
bolic disorders driven by the circadian clock. Moreover, syn-
chronizing the feeding-fasting cycle and sleep-wake cycle
with the timing of external signals can maintain a healthy
lifestyle that may in turn prevent metabolic diseases.
Furthermore, focusing on the crosstalk between circadian
rhythm and metabolism can help us to elucidate the pathogen-
esis of circadian clock associated disorders, which in turn, can
provide support in devising new strategies for prevention and
therapy of these disorders.
References
1. Allison KC, Ahima RS, O’Reardon JP, Dinges DF, Sharma V,
Cummings DE, Heo M, Martino NS, Stunkard AJ (2005)
Neuroendocrine profiles associated with energy intake, sleep,
and stress in the night eating syndrome. J Clin Endocrinol
Metab 90:6214–6217. https://doi.org/10.1210/jc.2005-1018
2. Anea CB, Zhang M, Stepp DW, Simkins GB, Reed G, Fulton DJ,
Rudic RD (2009) Vascular disease in mice with a dysfunctional
circadian clock. Circulation 119:1510–1517. https://doi.org/10.
1161/CIRCULATIONAHA.108.827477
3. Antunes LC, Levandovski R, Dantas G, Caumo W, Hidalgo MP
(2010) Obesity and shift work: chronobiological aspects. Nutr Res
Rev 23:155–168. https://doi.org/10.1017/S0954422410000016
4. Ashby T, Louis M (2019) Circadian misalignment and cardiovas-
cular risk. Cardiovasc Innov Appl 3:435–440. https://doi.org/10.
15212/CVIA.2017.0070
5. Asher G, Sassone-Corsi P (2015) Time for food: the intimate
interplay between nutrition, metabolism, and the circadian clock.
Cell 161:84–92. https://doi.org/10.1016/j.cell.2015.03.015
6. Astiz M, Heyde I, Oster H (2019) Mechanisms of communication
in the mammalian circadian timing system. Int J Mol Sci 20:343.
https://doi.org/10.3390/ijms20020343
7. Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI (2007)
Mechanisms underlying the resistance to diet-induced obesity in
germ-free mice. Proc Natl Acad Sci U S A 104:979–984. https://
doi.org/10.1073/pnas.0605374104
8. Balieiro LCT, Rossato LT, Waterhouse J, Paim SL, Mota MC,
Crispim CA (2014) Nutritional status and eating habits of bus
drivers during the day and night. Chronobiol Int 31:1123–1129.
https://doi.org/10.3109/07420528.2014.957299
9. Balsalobre A (2002) Clock genes in mammalian peripheral tis-
sues. Cell Tissue Res 309:193–199. https://doi.org/10.1007/
s00441-002-0585-0
10. Barclay JL, Husse J, Bode B, Naujokat N, Meyer-Kovac J,
Schmid SM, Lehnert H, Oster H (2012) Circadian desynchrony
promotes metabolic disruption in a mouse model of shiftwork.
PLoS One 7:e37150. https://doi.org/10.1371/journal.pone.
0037150
11. Barclay JL, Shostak A, Leliavski A, Tsang AH, Jöhren O, Müller-
Fielitz H, Landgraf D, Naujokat N, van der Horst GT, Oster H
(2013) High-fat diet-induced hyperinsulinemia and tissue-specific
insulin resistance in cry-deficient mice. Am J Physiol Endocrinol
Pflugers Arch - Eur J Physiol
Metab 304:E1053–E1063. https://doi.org/10.1152/ajpendo.
00512.2012
12. Bo S, Ciccone G, Durazzo M, Ghinamo L, Villois P, Canil S,
Gambino R, Cassader M, Gentile L, Cavallo-Perin P (2011)
Contributors to the obesity and hyperglycemia epidemics. A pro-
spective study in a population-based cohort. Int J Obes 35:1442–
1449. https://doi.org/10.1038/ijo.2011.5
13. Bonham MP, Bonnell EK, Huggins CE (2016) Energy intake of
shift workers compared to fixed day workers: a systematic review
and meta-analysis. Chronobiol Int 33:1086–1100. https://doi.org/
10.1080/07420528.2016.1192188
14. Buchvold HV, Pallesen S, Waage S, Bjorvatn BJ (2018) Shift
work schedule and night work load: effects on body mass index
– a four-year longitudinal study. Scand J Work Environ Health 44:
251–257. https://doi.org/10.5271/sjweh.3702
15. Bugge A, Feng D, Everett LJ, Briggs ER, Mullican SE, Wang F,
Jager J, Lazar MA (2012) Rev-erbα and Rev-erbβ coordinately
protect the circadian clock and normal metabolic function. Genes
Dev 26:657–667. https://doi.org/10.1101/gad.186858.112
16. Burch JB, Yost MG, Johnson W, Allen E (2005) Melatonin, sleep,
and shift work adaptation. J Occup Environ Med 47:893–901.
https://doi.org/10.1097/01.jom.0000177336.21147.9f
17. Cailotto C, Lei J, van der Vliet J, van Heijningen C, van Eden CG,
Kalsbeek A, Pévet P, Buijs RM (2009) Effects of nocturnal light
on (clock) gene expression in peripheral organs: a role for the
autonomic innervation of the liver. PLoS One 4:e5650. https://
doi.org/10.1371/journal.pone.0005650
18. Canaple L, Rambaud J, Dkhissi-Benyahya O, Ba R, Tan NS,
Michalik L, Delaunay F, Wahli W, Laudet V (2006) Reciprocal
regulation of brain and muscle Arnt-like protein 1 and peroxisome
proliferator-activated receptor α defines a novel positive feedback
loop in the rodent liver circadian clock. Mol Endocrinol 20:1715–
1727. https://doi.org/10.1210/me.2006-0052
19. Castro C, Briggs W, Paschos GK, FitzGerald GA, Griffin JL
(2015) A metabolomic study of adipose tissue in mice with a
disruption of the circadian system. Mol BioSyst 11:1897–1906.
https://doi.org/10.1039/c5mb00032g
20. Chaix A, Zarrinpar A, Miu P, Panda S (2014) Time-restricted
feeding is a preventative and therapeutic intervention against di-
verse nutritional challenges. Cell Metab 20:991–1005. https://doi.
org/10.1016/j.cmet.2014.11.001
21. Chaix A, Lin T, Le HD, Chang MW, Panda S (2019) Time-
restricted feeding prevents obesity and metabolic syndrome in
mice lacking a circadian clock. Cell Metab 29:303–319.e304.
https://doi.org/10.1016/j.cmet.2018.08.004
22. Chaudhari A, Gupta R, Makwana K, Kondratov R (2017)
Circadian clocks, diets and aging. Nutr Healthy Aging 4:101–
112. https://doi.org/10.3233/NHA-160006
23. Chen X, Devaraj S (2018) Gut microbiome in obesity, metabolic
syndrome, and diabetes. Curr Diab Rep 18:129. https://doi.org/10.
1007/s11892-018-1104-3
24. Chen L, Yang G (2014) PPARs integrate the mammalian clock
and energy metabolism. PPAR Res 2014:6–6. https://doi.org/10.
1155/2014/653017
25. Chen L, Yang G (2015) Recent advances in circadian rhythms in
cardiovascular system. Front Pharmacol 6:71–71. https://doi.org/
10.3389/fphar.2015.00071
26. Chung S, Son GH, Kim K (2011) Circadian rhythm of adrenal
glucocorticoid: its regulation and clinical implications. Biochim
Biophys Acta (BBA) - Mol Basis Dis 1812:581–591. https://doi.
org/10.1016/j.bbadis.2011.02.003
27. Chung H, Chou W, Sears DD, Patterson RE, Webster NJG, Ellies
LG (2016) Time-restricted feeding improves insulin resistance and
hepatic steatosis in a mouse model of postmenopausal obesity.
Metabolism 65:1743–1754. https://doi.org/10.1016/j.metabol.
2016.09.006
Pflugers Arch - Eur J Physiol
28. Cipolla-Neto J, Amaral FG, Afeche SC, Tan DX, Reiter RJ (2014)
Melatonin, energy metabolism, and obesity: a review. J Pineal Res
56:371–381. https://doi.org/10.1111/jpi.12137
29. Coomans CP, van den Berg SA, Houben T, van Klinken JB, van
den Berg R, Pronk AC, Havekes LM, Romijn JA, van Dijk KW,
Biermasz NR, Meijer JH (2013) Detrimental effects of constant
light exposure and high-fat diet on circadian energy metabolism
and insulin sensitivity. FASEB J 27:1721–1732. https://doi.org/10.
1096/fj.12-210898
30. Crnko S, Du Pré BC, Sluijter JPG, Van Laake LW (2019)
Circadian rhythms and the molecular clock in cardiovascular bi-
ology and disease. Nat Rev Cardiol 16:437–447. https://doi.org/
10.1038/s41569-019-0167-4
31. Curtis AM, Cheng Y, Kapoor S, Reilly D, Price TS, Fitzgerald GA
(2007) Circadian variation of blood pressure and the vascular re-
sponse to asynchronous stress. Proc Natl Acad Sci U S A 104:
3450–3455. https://doi.org/10.1073/pnas.0611680104
32. Dallmann R, Weaver DR (2010) Altered body mass regulation in
male mPeriod mutant mice on high-fat diet. Chronobiol Int 27:
1317–1328. https://doi.org/10.3109/07420528.2010.489166
33. Damiola F, Le Minh N, Preitner N, Kornmann B, Fleury-Olela F,
Schibler U (2000) Restricted feeding uncouples circadian oscilla-
tors in peripheral tissues from the central pacemaker in the supra-
chiasmatic nucleus. Genes Dev 14:2950–2961. https://doi.org/10.
1101/gad.183500
34. Di Lorenzo L, De Pergola G, Zocchetti C, L'Abbate N, Basso A,
Pannacciulli N, Cignarelli M, Giorgino R, Soleo L (2003) Effect
of shift work on body mass index: results of a study performed in
319 glucose-tolerant men working in a southern Italian industry.
Int J Obes 27:1353–1358. https://doi.org/10.1038/sj.ijo.0802419
35. Dubrovsky YV, Samsa WE, Kondratov RV (2010) Deficiency of
circadian protein CLOCK reduces lifespan and increases age-
related cataract development in mice. Aging 2:936–944. https://
doi.org/10.18632/aging.100241
36. Duez H, Staels B (2008) The nuclear receptors rev-erbs and RORs
integrate circadian rhythms and metabolism. Diab Vasc Dis Res 5:
82–88. https://doi.org/10.3132/dvdr.2008.0014
37. Duez H, Staels B (2009) Rev-erb-alpha: an integrator of circadian
rhythms and metabolism. J Appl Physiol (1985) 107:1972–1980.
https://doi.org/10.1152/japplphysiol.00570.2009
38. Eckel-Mahan K, Sassone-Corsi P (2013) Metabolism and the cir-
cadian clock converge. Physiol Rev 93:107–135. https://doi.org/
10.1152/physrev.00016.2012
39. Einarson TR, Acs A, Ludwig C, Panton UH (2018) Prevalence of
cardiovascular disease in type 2 diabetes: a systematic literature
review of scientific evidence from across the world in 2007-2017.
Cardiovasc Diabetol 17:83–83. https://doi.org/10.1186/s12933-
018-0728-6
40. El Aidy S, Merrifield CA, Derrien M, van Baarlen P, Hooiveld G,
Levenez F, Doré J, Dekker J, Holmes E, Claus SP, Reijngoud D-J,
Kleerebezem M (2013) The gut microbiota elicits a profound met-
abolic reorientation in the mouse jejunal mucosa during
conventionalisation. Gut 62:1306–1314. https://doi.org/10.1136/
gutjnl-2011-301955
41. Farhud D, Aryan Z (2018) Circadian rhythm, lifestyle and health:
a narrative review. Iran J Public Health 47:1068–1076
42. Federation IDJBIDF (2006) Diabetes atlas. Available via
DIALOG. https://www.idf.org/e-library/epidemiology-research/
diabetes-atlas/22-atlas-3rd-edition.html
43. Fisk AS, Tam SKE, Brown LA, Vyazovskiy VV, Bannerman DM,
Peirson SN (2018) Light and cognition: roles for circadian
rhythms, sleep, and arousal. Front Neurol 9. https://doi.org/10.
3389/fneur.2018.00056
44. Fonken LK, Nelson RJ (2014) The effects of light at night on
circadian clocks and metabolism. Endocr Rev 35:648–670.
https://doi.org/10.1210/er.2013-1051
45. Fonken LK, Workman JL, Walton JC, Weil ZM, Morris JS, Haim
A, Nelson RJ (2010) Light at night increases body mass by
shifting the time of food intake. Proc Natl Acad Sci U S A 107:
18664–18669. https://doi.org/10.1073/pnas.1008734107
46. Fonken LK, Lieberman RA, Weil ZM, Nelson RJ (2013) Dim
light at night exaggerates weight gain and inflammation associated
with a high-fat diet in male mice. Endocrinology 154:3817–3825.
https://doi.org/10.1210/en.2013-1121
47. Fonken LK, Weil ZM, Nelson RJ (2013) Dark nights reverse
metabolic disruption caused by dim light at night. Obesity
(Silver Spring) 21:1159–1164. https://doi.org/10.1002/oby.20108
48. Garaulet M, Gomez-Abellan P (2014) Timing of food intake and
obesity: a novel association. Physiol Behav 134:44–50. https://
doi.org/10.1016/j.physbeh.2014.01.001
49. Gómez-Abellán P, Hernández-Morante JJ, Luján JA, Madrid JA,
Garaulet M (2007) Clock genes are implicated in the human met-
abolic syndrome. Int J Obes 32:121–128. https://doi.org/10.1038/
sj.ijo.0803689
50. Gooley JJ, Chamberlain K, Smith KA, Khalsa SBS, Rajaratnam
SMW, Van Reen E, Zeitzer JM, Czeisler CA, Lockley SW (2011)
Exposure to room light before bedtime suppresses melatonin onset
and shortens melatonin duration in humans. J Clin Endocrinol
Metab 96:E463–E472. https://doi.org/10.1210/jc.2010-2098
51. Grimaldi B, Bellet MM, Katada S, Astarita G, Hirayama J, Amin
RH, Granneman JG, Piomelli D, Leff T, Sassone-Corsi P (2010)
PER2 controls lipid metabolism by direct regulation of PPARγ.
Cell Metab 12:509–520. https://doi.org/10.1016/j.cmet.2010.10.
005
52. Guerrero-Vargas NN, Espitia-Bautista E, Buijs RM, Escobar C
(2018) Shift-work: is time of eating determining metabolic health?
Evidence from animal models. Proc Nutr Soc 77:199–215. https://
doi.org/10.1017/S0029665117004128
53. Guillaumond F, Dardente H, Giguère V, Cermakian N (2005)
Differential control of Bmal1 circadian transcription by REV-
ERB and ROR nuclear receptors. J Biol Rhythm 20:391–403.
https://doi.org/10.1177/0748730405277232
54. Ha M, Park J (2005) Shiftwork and metabolic risk factors of car-
diovascular disease. J Occup Health 47:89–95. https://doi.org/10.
1539/joh.47.89
55. Haraguchi A, Fukuzawa M, Iwami S, Nishimura Y, Motohashi H,
Tahara Y, Shibata S (2018) Night eating model shows time-
specific depression-like behavior in the forced swimming test.
Sci Rep 8:1081. https://doi.org/10.1038/s41598-018-19433-8
56. Harfmann BD, Schroder EA, Kachman MT, Hodge BA, Zhang X,
Esser KA (2016) Muscle-specific loss of Bmal1 leads to disrupted
tissue glucose metabolism and systemic glucose homeostasis.
Skelet Muscle 6:12–12. https://doi.org/10.1186/s13395-016-
0082-x
57. Hatanaka F, Matsubara C, Myung J, Yoritaka T, Kamimura N,
Tsutsumi S, Kanai A, Suzuki Y, Sassone-Corsi P, Aburatani H,
Sugano S, Takumi T (2010) Genome-wide profiling of the core
clock protein BMAL1 targets reveals a strict relationship with
metabolism. Mol Cell Biol 30:5636–5648. https://doi.org/10.
1128/MCB.00781-10
58. Hirayama J, Alifu Y, Hamabe R, Yamaguchi S, Tomita J,
Maruyama Y, Asaoka Y, K-i N, Tamaru T, Takamatsu K,
Takamatsu N, Hattori A, Nishina S, Azuma N, Kawahara A,
Kume K, Nishina H (2019) The clock components Period2,
Cryptochrome1a, and Cryptochrome2a function in establishing
light-dependent behavioral rhythms and/or total activity levels in
zebrafish. Sci Rep 9:196. https://doi.org/10.1038/s41598-018-
37879-8
59. Ho JM, Barf RP, Opp MR (2016) Effects of sleep disruption and
high fat intake on glucose metabolism in mice.
Psychoneuroendocrinology 68:47–56. https://doi.org/10.1016/j.
psyneuen.2016.02.024

60. Hu D, Mao Y, Xu G, Liao W, Ren J, Yang H, Yang J, Sun L, Chen
H, Wang W, Wang Y, Sang X, Lu X, Zhang H, Zhong S (2019)
Time-restricted feeding causes irreversible metabolic disorders
and gut microbiota shift in pediatric mice. Pediatr Res 85:518–
526. https://doi.org/10.1038/s41390-018-0156-z
61. Huang PL (2009) A comprehensive definition for metabolic syn-
drome. Dis Model Mech 2:231–237. https://doi.org/10.1242/
dmm.001180
62. Huang R-C (2018) The discoveries of molecular mechanisms for
the circadian rhythm: the 2017 Nobel Prize in Physiology or
Medicine. Biom J 41:5–8. https://doi.org/10.1016/j.bj.2018.02.
003
63. Husse J, Eichele G, Oster H (2015) Synchronization of the mam-
malian circadian timing system: light can control peripheral clocks
independently of the SCN clock. BioEssays 37:1119–1128.
https://doi.org/10.1002/bies.201500026
64. Ikeda R, Tsuchiya Y, Koike N, Umemura Y, Inokawa H, Ono R,
Inoue M, Sasawaki Y, Grieten T, Okubo N, Ikoma K, Fujiwara H,
Kubo T, Yagita K (2019) REV-ERBα and REV-ERBβ function as
key factors regulating mammalian circadian output. Sci Rep 9:
10171. https://doi.org/10.1038/s41598-019-46656-0
65. Itani O, Kaneita Y, Murata A, Yokoyama E, Ohida T (2011)
Association of onset of obesity with sleep duration and shift work
among Japanese adults. Sleep Med 12:341–345. https://doi.org/
10.1016/j.sleep.2010.09.007
66. Jagannath A, Taylor L, Wakaf Z, Vasudevan SR, Foster RG
(2017) The genetics of circadian rhythms, sleep and health. Hum
Mol Genet 26:R128–R138. https://doi.org/10.1093/hmg/ddx240
67. Jing E, Emanuelli B, Hirschey MD, Boucher J, Lee KY, Lombard
D, Verdin EM, Kahn CR (2011) Sirtuin-3 (Sirt3) regulates skeletal
muscle metabolism and insulin signaling via altered mitochondrial
oxidation and reactive oxygen species production. Proc Natl Acad
Sci U S A 108:14608–14613. https://doi.org/10.1073/pnas.
1111308108
68. Jones SE, Lane JM, Wood AR, van Hees VT, Tyrrell J, Beaumont
RN, Jeffries AR, Dashti HS, Hillsdon M, Ruth KS, Tuke MA,
Yaghootkar H, Sharp SA, Jie Y, Thompson WD, Harrison JW,
Dawes A, Byrne EM, Tiemeier H, Allebrandt KV, Bowden J,
Ray DW, Freathy RM, Murray A, Mazzotti DR, Gehrman PR,
Lawlor DA, Frayling TM, Rutter MK, Hinds DA, Saxena R,
Weedon MN (2019) Genome-wide association analyses of
chronotype in 697,828 individuals provides insights into circadian
rhythms. Nat Commun 10:343. https://doi.org/10.1038/s41467-
018-08259-7
69. Kalsbeek A, Fliers E, Romijn JA, la Fleur SE, Wortel J, Bakker O,
Endert E, Buijs RM (2001) The suprachiasmatic nucleus generates
the diurnal changes in plasma leptin levels. Endocrinology 142:
2677–2685. https://doi.org/10.1210/endo.142.6.8197
70. Karatsoreos IN, Bhagat S, Bloss EB, Morrison JH, McEwen BS
(2011) Disruption of circadian clocks has ramifications for metab-
olism, brain, and behavior. Proc Natl Acad Sc U S A 108:1657–
1662. https://doi.org/10.1073/pnas.1018375108
71. Karlsson B, Knutsson A, Lindahl B (2001) Is there an association
between shift work and having a metabolic syndrome? Results
from a population based study of 27 485 people. Occup Environ
Med 58:747–752. https://doi.org/10.1136/oem.58.11.747
72. Kim M-J, Son K-H, Park H-Y, Choi D-J, Yoon C-H, Lee H-Y, Cho
E-Y, Cho M-C (2013) Association between shift work and obesity
among female nurses: Korean nurses’ survey. BMC Public Health
13:1204. https://doi.org/10.1186/1471-2458-13-1204
73. Kojetin DJ, Burris TP (2014) REV-ERB and ROR nuclear recep-
tors as drug targets. Nat Rev Drug Discov 13:197–216. https://doi.
org/10.1038/nrd4100
74. Lamia KA, Evans RM (2010) Metabolism Tick, tock, a β-cell
clock. Nature 466(7306):571–572. https://doi.org/10.1038/
466571a
Pflugers Arch - Eur J Physiol
75. Lamia KA, Storch K-F, Weitz CJ (2008) Physiological signifi-
cance of a peripheral tissue circadian clock. Proc Natl Acad Sci
U S A 105:15172–15177. https://doi.org/10.1073/pnas.
0806717105
76. Larsson E, Tremaroli V, Lee YS, Koren O, Nookaew I, Fricker A,
Nielsen J, Ley RE, Bäckhed F (2012) Analysis of gut microbial
regulation of host gene expression along the length of the gut and
regulation of gut microbial ecology through MyD88. Gut 61:
1124–1131. https://doi.org/10.1136/gutjnl-2011-301104
77. Lebeche D, Davidoff AJ, Hajjar RJ (2008) Interplay between im-
paired calcium regulation and insulin signaling abnormalities in
diabetic cardiomyopathy. Nat Clin Pract Cardiovasc Med 5:715–
724. https://doi.org/10.1038/ncpcardio1347
78. Leone TC, Weinheimer CJ, Kelly DP (1999) A critical role for the
peroxisome proliferator-activated receptor α (PPARα) in the cel-
lular fasting response: the PPARα-null mouse as a model of fatty
acid oxidation disorders. Proc Natl Acad Sci U S A 96:7473–
7478. https://doi.org/10.1073/pnas.96.13.7473
79. Leone V, Gibbons Sean M, Martinez K, Hutchison Alan L, Huang
Edmond Y, Cham Candace M, Pierre Joseph F, Heneghan Aaron
F, Nadimpalli A, Hubert N, Zale E, Wang Y, Huang Y, Theriault B,
Dinner Aaron R, Musch Mark W, Kudsk Kenneth A, Prendergast
Brian J, Gilbert Jack A, Chang Eugene B (2015) Effects of diurnal
variation of gut microbes and high-fat feeding on host circadian
clock function and metabolism. Cell Host Microbe 17:681–689.
https://doi.org/10.1016/j.chom.2015.03.006
80. Li X (2013) SIRT1 and energy metabolism. Acta Biochim
Biophys Sin Shanghai 45:51–60. https://doi.org/10.1093/abbs/
gms108
81. Liang X, Bushman FD, FitzGerald GA (2015) Rhythmicity of the
intestinal microbiota is regulated by gender and the host circadian
clock. Proc Natl Acad Sci U S A 112:10479–10484. https://doi.
org/10.1073/pnas.1501305112
82. Liu S, Downes M, Evans RM (2015) Metabolic regulation by
nuclear receptors. Innovative medicine. Springer, Japan, p 25-37
83. Liu Q, Shi J, Duan P, Liu B, Li T, Wang C, Li H, Yang T, Gan Y,
Wang X, Cao S, Lu Z (2018) Is shift work associated with a higher
risk of overweight or obesity? A systematic review of observation-
al studies with meta-analysis. Int J Epidemiol 47:1956–1971.
https://doi.org/10.1093/ije/dyy079
84. Manoogian ENC, Panda S (2017) Circadian rhythms, time-
restricted feeding, and healthy aging. Ageing Res Rev 39:59–67.
https://doi.org/10.1016/j.arr.2016.12.006
85. Marcheva B, Ramsey KM, Buhr ED, Kobayashi Y, Su H, Ko CH,
Ivanova G, Omura C, Mo S, Vitaterna MH, Lopez JP, Philipson
LH, Bradfield CA, Crosby SD, JeBailey L, Wang X, Takahashi
JS, Bass J (2010) Disruption of the clock components CLOCK
and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466:
627–631. https://doi.org/10.1038/nature09253
86. Marcheva B, Ramsey KM, Peek CB, Affinati A, Maury E, Bass J
(2013) Circadian clocks and metabolism. Handb Exp Pharmacol
217:127–155. https://doi.org/10.1007/978-3-642-25950-0_6
87. Martinez-Guryn K, Hubert N, Frazier K, Urlass S, Musch MW,
Ojeda P, Pierre JF, Miyoshi J, Sontag TJ, Cham CM, Reardon CA,
Leone V, Chang EB (2018) Small intestine microbiota regulate
host digestive and absorptive adaptive responses to dietary lipids.
Cell Host Microbe 23:458–469.e455. https://doi.org/10.1016/j.
chom.2018.03.011
88. Masri S (2015) Sirtuin-dependent clock control: new advances in
metabolism, aging and cancer. Curr Opin Clin Nutr Metab Care
18:521–527. https://doi.org/10.1097/MCO.0000000000000219
89. Masuki S, Todo T, Nakano Y, Okamura H, Nose H (2005)
Reduced alpha-adrenoceptor responsiveness and enhanced baro-
reflex sensitivity in cry-deficient mice lacking a biological clock. J
Physiol 566:213–224. https://doi.org/10.1113/jphysiol.2005.
086728
Pflugers Arch - Eur J Physiol
90. Maury E (2019) Off the clock: from circadian disruption to met-
abolic disease. Int J Mol Sci 20:1597. https://doi.org/10.3390/
ijms20071597
91. Maury E, Ramsey KM, Bass J (2010) Circadian rhythms and
metabolic syndrome: from experimental genetics to human dis-
ease. Circ Res 106(3):447–462. https://doi.org/10.1161/
CIRCRESAHA.109.208355
92. McHill AW, Wright KP Jr (2017) Role of sleep and circadian
disruption on energy expenditure and in metabolic predisposition
to human obesity and metabolic disease. Obes Rev 18:15–24.
https://doi.org/10.1111/obr.12503
93. McHill AW, Melanson EL, Higgins J, Connick E, Moehlman TM,
Stothard ER, Wright KP (2014) Impact of circadian misalignment
on energy metabolism during simulated nightshift work. Proc Natl
Acad Sci U S A 111:17302–17307. https://doi.org/10.1073/pnas.
1412021111
94. Milano W, De Rosa M, Milano L, Capasso A (2012) Night eating
syndrome: an overview. J Pharm Pharmacol 64:2–10. https://doi.
org/10.1111/j.2042-7158.2011.01353.x
95. Morris CJ, Purvis TE, Mistretta J, Scheer FAJL (2016) Effects of
the internal circadian system and circadian misalignment on glu-
cose tolerance in chronic shift workers. J Clin Endocrinol Metab
101:1066–1074. https://doi.org/10.1210/jc.2015-3924
96. Mure LS, Le HD, Benegiamo G, Chang MW, Rios L, Jillani N,
Ngotho M, Kariuki T, Dkhissi-Benyahya O, Cooper HM, Panda S
(2018) Diurnal transcriptome atlas of a primate across major neu-
ral and peripheral tissues. Science 359:eaao0318. https://doi.org/
10.1126/science.aao0318
97. Oishi K, Miyazaki K, Kadota K, Kikuno R, Nagase T, G-i A,
Ohkura N, Azama T, Mesaki M, Yukimasa S, Kobayashi H,
Iitaka C, Umehara T, Horikoshi M, Kudo T, Shimizu Y, Yano
M, Monden M, Machida K, Matsuda J, Horie S, Todo T, Ishida
N (2003) Genome-wide expression analysis of mouse liver reveals
CLOCK-regulated circadian output genes. J Biol Chem 278:
41519–41527. https://doi.org/10.1074/jbc.M304564200
98. Oishi K, Shirai H, Ishida N (2005) CLOCK is involved in the
circadian transactivation of peroxisome-proliferator-activated re-
ceptor alpha (PPARalpha) in mice. Biochem J 386:575–581.
https://doi.org/10.1042/BJ20041150
99. Okano S, Akashi M, Hayasaka K, Nakajima O (2009) Unusual
circadian locomotor activity and pathophysiology in mutant
CRY1 transgenic mice. Neurosci Lett 451:246–251. https://doi.
org/10.1016/j.neulet.2009.01.014
100. Opperhuizen A-L, van Kerkhof LWM, Proper KI, Rodenburg W,
Kalsbeek A (2015) Rodent models to study the metabolic effects
of shiftwork in humans. Front Pharmacol 6:50–50. https://doi.org/
10.3389/fphar.2015.00050
101. Parkar SG, Kalsbeek A, Cheeseman JF (2019) Potential role for
the gut microbiota in modulating host circadian rhythms and met-
abolic health. Microorganisms 7:41. https://doi.org/10.3390/
microorganisms7020041
102. Parkes KR (2002) Shift work and age as interactive predictors of
body mass index among offshore workers. Scand J Work Environ
Health 28:64–71. https://doi.org/10.5271/sjweh.648
103. Paschos GK, FitzGerald GA (2017) Circadian clocks and metab-
olism: implications for microbiome and aging. Trends Genet 33:
760–769. https://doi.org/10.1016/j.tig.2017.07.010
104. Paschos GK, Ibrahim S, Song W-L, Kunieda T, Grant G, Reyes
TM, Bradfield CA, Vaughan CH, Eiden M, Masoodi M, Griffin
JL, Wang F, Lawson JA, FitzGerald GA (2012) Obesity in mice
with adipocyte-specific deletion of clock component Arntl. Nat
Med 18:1768–1777. https://doi.org/10.1038/nm.2979
105. Potter GDM, Skene DJ, Arendt J, Cade JE, Grant PJ, Hardie LJ
(2016) Circadian rhythm and sleep disruption: causes, metabolic
consequences, and countermeasures. Endocr Rev 37:584–608.
https://doi.org/10.1210/er.2016-1083
106. Preitner N, Damiola F, Luis Lopez M, Zakany J, Duboule D,
Albrecht U, Schibler U (2002) The orphan nuclear receptor
REV-ERBα controls circadian transcription within the positive
limb of the mammalian circadian oscillator. Cell 110:251–260.
https://doi.org/10.1016/S0092-8674(02)00825-5
107. Rana S, Mahmood S (2010) Circadian rhythm and its role in
malignancy. J Circadian Rhythms 8:3–3. https://doi.org/10.1186/
1740-3391-8-3
108. Reppert SM, Weaver DR (2002) Coordination of circadian timing
in mammals. Nature 418:935–941. https://doi.org/10.1038/
nature00965
109. Rothschild J, Hoddy KK, Jambazian P, Varady KA (2014) Time-
restricted feeding and risk of metabolic disease: a review of human
and animal studies. Nutr Rev 72:308–318. https://doi.org/10.1111/
nure.12104
110. Ruiter M, La Fleur SE, van Heijningen C, van der Vliet J,
Kalsbeek A, Buijs RM (2003) The daily rhythm in plasma gluca-
gon concentrations in the rat is modulated by the biological clock
and by feeding behavior. Diabetes 52:1709–1715. https://doi.org/
10.2337/diabetes.52.7.1709
111. Sadacca LA, Lamia KA, deLemos AS, Blum B, Weitz CJ (2011)
An intrinsic circadian clock 54:120-124. Of the pancreas is re-
quired for normal insulin release and glucose homeostasis in mice.
Diabetologica. https://doi.org/10.1007/s00125-010-1920-8
112. Sakamoto K, Nagase T, Fukui H, Horikawa K, Okada T, Tanaka
H, Sato K, Miyake Y, Ohara O, Kako K, Ishida N (1998)
Multitissue circadian expression of rat periodHomolog (rPer2)
mRNA is governed by the mammalian circadian clock, the supra-
chiasmatic nucleus in the brain. J Biol Chem 273:27039–27042.
https://doi.org/10.1074/jbc.273.42.27039
113. Salgado-Delgado RC, Saderi N, Basualdo MC, Guerrero-Vargas
NN, Escobar C, Buijs RM (2013) Shift work or food intake during
the rest phase promotes metabolic disruption and desynchrony of
liver genes in male rats. PLoS One 8:e60052. https://doi.org/10.
1371/journal.pone.0060052
114. Scheer FAJL, Hilton MF, Mantzoros CS, Shea SA (2009) Adverse
metabolic and cardiovascular consequences of circadian misalign-
ment. Proc Natl Acad Sci U S A 106:4453–4458. https://doi.org/
10.1073/pnas.0808180106
115. Scott EM, Carter AM, Grant PJ (2007) Association between poly-
morphisms in the clock gene, obesity and the metabolic syndrome
in man. Int J Obes 32:658–662. https://doi.org/10.1038/sj.ijo.
0803778
116. Serin Y, Acar Tek N (2019) Effect of circadian rhythm on meta-
bolic processes and the regulation of energy balance. Ann Nutr
Metab 74:322–330. https://doi.org/10.1159/000500071
117. Serón-Ferré M, Forcelledo ML, Torres-Farfan C, Valenzuela FJ,
Rojas A, Vergara M, Rojas-Garcia PP, Recabarren MP, Valenzuela
GJ (2013) Impact of chronodisruption during primate pregnancy
on the maternal and newborn temperature rhythms. PLoS One 8:
e57710. https://doi.org/10.1371/journal.pone.0057710
118. Shimba S, Ogawa T, Hitosugi S, Ichihashi Y, Nakadaira Y,
Kobayashi M, Tezuka M, Kosuge Y, Ishige K, Ito Y, Komiyama
K, Okamatsu-Ogura Y, Kimura K, Saito M (2011) Deficient of a
clock gene, brain and muscle Arnt-like protein-1 (BMAL1), in-
duces dyslipidemia and ectopic fat formation. PLoS One 6:
e25231. https://doi.org/10.1371/journal.pone.0025231
119. Skene DJ, Skornyakov E, Chowdhury NR, Gajula RP, Middleton
B, Satterfield BC, Porter KI, Van Dongen HPA, Gaddameedhi S
(2018) Separation of circadian- and behavior-driven metabolite
rhythms in humans provides a window on peripheral oscillators
and metabolism. Proc Natl Acad Sci U S A 115:7825–7830.
https://doi.org/10.1073/pnas.1801183115
120. Shi S-q, Ansari TS, McGuinness Owen P, Wasserman David H,
Johnson Carl H (2013) Circadian disruption leads to insulin

resistance and obesity. Curr Biol 23:372–381. https://doi.org/10.
1016/j.cub.2013.01.048
121. Stenvers DJ, Scheer FAJL, Schrauwen P, la Fleur SE, Kalsbeek A
(2019) Circadian clocks and insulin resistance. Nat Rev
Endocrinol 15:75–89. https://doi.org/10.1038/s41574-018-0122-1
122. Sun L, Wang Y, Song Y, Cheng X-R, Xia S, Rahman MRT, Shi Y,
Le G (2015) Resveratrol restores the circadian rhythmic disorder
of lipid metabolism induced by high-fat diet in mice. Biochem
Biophys Res Commun 458:86–91. https://doi.org/10.1016/j.bbrc.
2015.01.072
123. Sun M, Feng W, Wang F, Li P, Li Z, Li M, Tse G, Vlaanderen J,
Vermeulen R, Tse LA (2018) Meta-analysis on shift work and
risks of specific obesity types. Obes Rev 19:28–40. https://doi.
org/10.1111/obr.12621
124. Sutton EF, Beyl R, Early KS, Cefalu WT, Ravussin E, Peterson
CM (2018) Early time-restricted feeding improves insulin sensi-
tivity, blood pressure, and oxidative stress even without weight
loss in men with prediabetes. Cell Metab 27:1212–1221.e1213.
https://doi.org/10.1016/j.cmet.2018.04.010
125. Sweeney E, Yu ZM, Dummer TJB, Cui Y, DeClercq V, Forbes C,
Grandy SA, Keats M, Parker L, Adisesh A (2019) The relationship
between anthropometric measures and cardiometabolic health in
shift work: findings from the Atlantic PATH cohort study. Int Arch
Occup Environ Health 93(1):67–76. https://doi.org/10.1007/
s00420-019-01459-8
126. Takahashi JS, Hong H-K, Ko CH, McDearmon EL (2008) The
genetics of mammalian circadian order and disorder: implications
for physiology and disease. Nat Rev Genet 9:764–775. https://doi.
org/10.1038/nrg2430
127. Tamai TK, Vardhanabhuti V, Foulkes NS, Whitmore D (2004)
Early embryonic light detection improves survival. Curr Biol 14:
R104–R105
128. Tamai TK, Carr AJ, Whitmore D (2005) Zebrafish circadian
clocks: cells that see light. Biochem Soc Trans 33:962–966.
https://doi.org/10.1042/BST0330962
129. Thaiss Christoph A, Zeevi D, Levy M, Zilberman-Schapira G,
Suez J, Tengeler Anouk C, Abramson L, Katz Meirav N, Korem
T, Zmora N, Kuperman Y, Biton I, Gilad S, Harmelin A, Shapiro
H, Halpern Z, Segal E, Elinav E (2014) Transkingdom control of
microbiota diurnal oscillations promotes metabolic homeostasis.
Cell 159:514–529. https://doi.org/10.1016/j.cell.2014.09.048
130. Thosar SS, Butler MP, Shea SA (2018) Role of the circadian
system in cardiovascular disease. J Clin Investig 128:2157–
2167. https://doi.org/10.1172/JCI80590
131. Turek FW, Joshu C, Kohsaka A, Lin E, Ivanova G, McDearmon
E, Laposky A, Losee-Olson S, Easton A, Jensen DR, Eckel RH,
Takahashi JS, Bass J (2005) Obesity and metabolic syndrome in
circadian clock mutant mice. Science 308:1043–1045. https://doi.
org/10.1126/science.1108750
132. Valenzuela FJ, Torres-Farfan C, Richter HG, Mendez N, Campino
C, Torrealba F, Valenzuela GJ, Serón-Ferré M (2008) Clock gene
expression in adult primate suprachiasmatic nuclei and adrenal: is
the adrenal a peripheral clock responsive to melatonin?
Endocrinology 149:1454–1461. https://doi.org/10.1210/en.2007-
1518
133. Valenzuela FJ, Vera J, Venegas C, Muñoz S, Oyarce S, Muñoz K,
Lagunas C (2016) Evidences of polymorphism associated with
circadian system and risk of pathologies: a review of the literature.
Int J Endocrinol 2016:12–12. https://doi.org/10.1155/2016/
2746909
134. Villanueva JE, Livelo C, Trujillo AS, Chandran S, Woodworth B,
Andrade L, Le HD, Manor U, Panda S, Melkani GC (2019) Time-
restricted feeding restores muscle function in Drosophila models
Pflugers Arch - Eur J Physiol
of obesity and circadian-rhythm disruption. Nat Commun 10.
https://doi.org/10.1038/s41467-019-10563-9
135. Voigt RM, Forsyth CB, Green SJ, Engen PA, Keshavarzian A
(2016) Circadian rhythm and the gut microbiome. Int Rev
Neurobiol 131:193–205. https://doi.org/10.1016/bs.irn.2016.07.
002
136. Voigt RM, Summa KC, Forsyth CB, Green SJ, Engen P, Naqib A,
Vitaterna MH, Turek FW, Keshavarzian A (2016) The circadian
clock mutation promotes intestinal Dysbiosis. Alcohol Clin Exp
Res 40:335–347. https://doi.org/10.1111/acer.12943
137. Westermeier F, Sáez PJ, Villalobos-Labra R, Sobrevia L, Farías-
Jofré M (2014) Programming of fetal insulin resistance in preg-
nancies with maternal obesity by ER stress and inflammation.
Biomed Res Int 2014:13–13. https://doi.org/10.1155/2014/
917672
138. Wyse CA, Celis Morales CA, Graham N, Fan Y, Ward J, Curtis
AM, Mackay D, Smith DJ, Bailey MES, Biello S, Gill JMR, Pell
JP (2017) Adverse metabolic and mental health outcomes associ-
ated with shiftwork in a population-based study of 277,168
workers in UK biobank. Ann Med 49:411–420. https://doi.org/
10.1080/07853890.2017.1292045
139. Xie Z, Su W, Liu S, Zhao G, Esser K, Schroder EA, Lefta M,
Stauss HM, Guo Z, Gong MC (2015) Smooth-muscle BMAL1
participates in blood pressure circadian rhythm regulation. J Clin
Investig 125:324–336. https://doi.org/10.1172/JCI76881
140. Yang X, Downes M, Yu RT, Bookout AL, He W, Straume M,
Mangelsdorf DJ, Evans RM (2006) Nuclear receptor expression
links the circadian clock to metabolism. Cell 126:801–810. https://
doi.org/10.1016/j.cell.2006.06.050
141. Yang S, Liu A, Weidenhammer A, Cooksey RC, McClain D, Kim
MK, Aguilera G, Abel ED, Chung JH (2009) The role of mPer2
clock gene in glucocorticoid and feeding rhythms. Endocrinology
150:2153–2160. https://doi.org/10.1210/en.2008-0705
142. Yang G, Jia Z, Aoyagi T, McClain D, Mortensen RM, Yang T
(2012) Systemic PPARγ deletion impairs circadian rhythms of
behavior and metabolism. PLoS One 7:e38117. https://doi.org/
10.1371/journal.pone.0038117
143. Yoshida J, Eguchi E, Nagaoka K, Ito T, Ogino K (2018)
Association of night eating habits with metabolic syndrome and
its components: a longitudinal study. BMC Public Health 18:
1366. https://doi.org/10.1186/s12889-018-6262-3
144. Yu JH, Yun C-H, Ahn JH, Suh S, Cho HJ, Lee SK, Yoo HJ, Seo
JA, Kim SG, Choi KM, Baik SH, Choi DS, Shin C, Kim NH
(2015) Evening chronotype is associated with metabolic disorders
and body composition in middle-aged adults. J Clin Endocrinol
Metab 100:1494–1502. https://doi.org/10.1210/jc.2014-3754
145. Zhang R, Lahens NF, Ballance HI, Hughes ME, Hogenesch JB
(2014) A circadian gene expression atlas in mammals: implica-
tions for biology and medicine. Proc Natl Acad Sci U S A 111:
16219–16224. https://doi.org/10.1073/pnas.1408886111
146. Zhao Y, Zhang Y, Zhou M, Wang S, Hua Z, Zhang J (2012) Loss
of mPer2 increases plasma insulin levels by enhanced glucose-
stimulated insulin secretion and impaired insulin clearance in
mice. FEBS Lett 586:1306–1311. https://doi.org/10.1016/j.
febslet.2012.03.034
147. Zhou S, Tang X, Chen H-Z (2018) Sirtuins and insulin resistance.
Front Endocrinol 9:748. https://doi.org/10.3389/fendo.2018.
00748
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