J Pharmacol Sci 124, 320 – 335 (2014) Journal of Pharmacological Sciences

© The Japanese Pharmacological Society

Critical Review

Chrono-biology, Chrono-pharmacology, and Chrono-nutrition

Yu Tahara1 and Shigenobu Shibata1,*
1
Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University,
Tokyo 162-8480, Japan

Received October 25, 2013; Accepted January 5, 2014

Abstract.  The circadian clock system in mammals drives many physiological processes
including the daily rhythms of sleep–wake behavior, hormonal secretion, and metabolism. This
system responds to daily environmental changes, such as the light–dark cycle, food intake, and
drug administration. In this review, we focus on the central and peripheral circadian clock systems
in response to drugs, food, and nutrition. We also discuss the adaptation and anticipation mecha-
nisms of our body with regard to clock system regulation of various kinetic and dynamic pathways,
including absorption, distribution, metabolism, and excretion of drugs and nutrients. “Chrono-
pharmacology” and “chrono-nutrition” are likely to become important research fields in chrono-
biological studies.

Keywords: circadian rhythm, Period 2 gene, liver, obesity, metabolism

1. Molecular mechanisms of the circadian clock local clock in the peripheral tissues through multiple
system pathways involving neural and hormonal functions
(2, 3). The molecular mechanism of the circadian system
The circadian clock system has been widely main- in mammals has been well studied over the past two
tained in many species, from prokaryotes to mammals. decades. The transcriptional–translational feedback loop
“Circadian” means “around [a] day” in Latin, and there- of the major clock genes Bmal1, Clock, Per1/2, and
fore “circadian rhythm” refers to a cycle of approximate Cry1/2 is the main component of the circadian system (2)
24 h. The earth rotates once every 24 h, and the circadian (Fig. 1A). Bmal1 and Clock, which are transcriptional
system has evolved to adjust functions and behavior to activators, play a positive role in activating the Per and
this cycle in order to efficiently utilize sunlight for Cry genes through a specific promoter sequence known
photosynthesis in the case of plants and cyanobacteria as the E-box. Per and Cry are translated into proteins in
and to obtain food in the case of animals. One of the the cytoplasm and are then transported back into the
most important features of our circadian system is that nucleus after interacting with each other, and they sub­
circadian clocks can endogenously maintain time under sequently stop their transcription by binding to BMAL1
constant darkness and without external stimuli, suggesting and CLOCK. Thus, Per and Cry are rhythmically
that our body has its own internal clocks. In 1972, Moore expressed over a 24-h period. This transcriptional regula-
and Eichler (1) investigated the effects of destroying the tion induces rhythmic expression of approximately 10%
suprachiasmatic nucleus (SCN) in the rat hypothalamus. of all genes in each peripheral cell (4 – 6). In addition to
Their results revealed the loss of sleep-wake cycles and such transcriptional regulation of the circadian clock,
corticosterone rhythms. Since then, the SCN is regarded post-transcriptional regulation and translational regula-
as the location of the master clock system in mammals. tion have recently been reported to play important
The SCN receives light–dark information directly roles in maintaining circadian rhythms. Genome-wide
through the retinal–hypothalamic tract and organizes the RNA-seq and Chip-seq analyses found that only 22%
of the rhythmically oscillating messenger RNAs are
*Corresponding author.  [email protected]
driven by de novo transcription, with RNA polymerase II
Published online in J-STAGE on February 27, 2014
doi: 10.1254/jphs.13R06CR recruitment and chromatin remodeling also exhibiting
such rhythms (7). Furthermore, it was reported that the
Invited article non-transcriptional redox cycle has a 24-h rhythm in

320

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 Chrono-pharmacology 321

Fig. 1.  Framework of the Introduction. A) Sche-

matic diagram of feedback loop of circadian
clock genes. B, C) Schematic diagram of “chrono-
pharmacology (B)” and “chrono-nutrition (C)”,
respectively. In both strategies, there are two
aspects. The first is that circadian changes affect
functions such as the absorption, distribution,
metabolism, and excretion of drugs or nutrients.
Considering these factors when determining the
timing, amount, and composition of drug adminis-
tration or food intake can be beneficial for enhanc-
ing the power of the drug and functional food
effects and for improving human health and dis-
eases. The second aspect is that similar to light
stimulation, drugs and nutrients can serve as
stimuli for changing the phase of circadian clocks.

human red blood cells, which have no DNA or nucleus. A particular feature of the circadian system is “entrain-
This redox rhythm of peroxiredoxins was shown not only ment to 24-h oscillation” by external or internal signals
in human blood cells, but also in other eukaryotic cells because the oscillation period of the circadian clock
(8, 9). In the SCN, the redox state regulates the rhythmic is not precisely 24 h, but approximately 24 h. Light
output activity concerning the neuronal firing of SCN information obtained via retinal input is the typical
neurons (10). These observations indicate that our under- external entrainable factor in mammals. In addition to
standing of the circadian clock system is expanding light, entrainable factors include food, temperature,
and that the system employs complicated processes to exercise, and drugs. Among these factors, food is the best
generate accurate clock rhythms. For an important synchronizer (i.e., comparable with light) (11 – 14).
issue, the circadian expression phases of clock and clock-
controlled genes are anti-phase between human (diurnal) 2. Chrono-pharmacology and chrono-nutrition
and mice/rats (nocturnal) in the brain excluding the SCN
and peripheral tissues. Whereas, in the SCN, the phases A well-known aspect of circadian rhythm is so-called
of clock gene expression rhythms are same in both “chrono-pharmacology”, which is used to determine the
diurnal and nocturnal animals. Although the mechanism timing of drug administration in relation to circadian
of this anti-phasic change from the SCN to the other changes in targeted kinase activity, the protein quantities
organs is still unknown, the findings of many circadian needed to enhance the potency of a drug, and/or the
functions in rodents could be applied to humans by absorption and excretion of a drug (Fig. 1B). Chrono-
changing the phase of circadian regulation to the anti- pharmacology enables us to maintain or improve human
phase of it. health by speculating the state of metabolic activity
322 Y Tahara and S Shibata

Fig. 2.  A framework of the aspect of chrono-pharmacology: circadian regulation of drug functions. Drug absorption, distribu-
tion, metabolism, and excretion (ADME) and drug-targeted genes are influenced by the circadian system. In each aspect, represen-
tative factors and keywords that we discussed in this review are indicated in this figure.

and it also enables optimal timing of food intake by studies have provided evidence showing the importance
understanding the circadian changes in the digestive of the circadian clocks in gut physiology (15 – 19).
system. In another aspect of chrono-pharmacology, many Drug absorption is dependent on the drug transporters
drugs have been investigated for the powerful tool of expressed in the gut. Several lipid transport proteins
regulating the circadian system in mammals. These drugs including microsomal transport protein, which is impor-
can be useful for the therapy of circadian disorders, tant for fatty acid transport, are regulated by circadian
such as circadian rhythm sleep disorders and jet lag. clocks, suggesting that lipophilic drugs may also be
Recently, the term “chrono-nutrition” has also been used under their control in mice (20 – 22). Thus, circadian
to refer to the relationship between food and the circadian patterns of absorption are especially pronounced in
clock system (Fig. 1C). In addition, we can change the lipophilic drugs, and absorption is higher during the
timing of our internal clock by altering the timing of food active phase than at the inactive phase in mice (23).
intake. Consequently, chrono-nutrition has been defined Multi-drug-resistance 1a, a xenobiotic efflux pump,
to encompass the following two aspects: i) timing of food exhibits a circadian pattern of action, and its gene
intake or contribution of food components to the mainte- expression is directly regulated by core clock genes in
nance of health and ii) timing of food intake or contribu- mice (24, 25). Several drug efflux pumps such as Mct1,
tion of food components to rapid changes in or resetting Mrp2, Pept1, and Bcrp also show circadian expression
of our system of internal clocks. Therefore, as is the patterns in rats (26). As a result of diurnal variations in
case in chrono-pharmacology, chrono-nutrition will be the functions of transporters and efflux pumps, drug
a common strategy to keep our health through absorption is sensitive to the time of administration.
the circadian rhythm system. In this review we focused The following three factors may contribute to the
on these four aspects of chrono-pharmacology and volume of distribution of a given drug: concentration,
chrono-nutrition in each section. albumin binding affinity, and lipophilicity. The degree of
protein binding between drugs varies in a diurnal manner
3. Chrono-pharmacology: circadian regulation of and correlates with changes in plasma albumin levels
drug functions (27).
The xenobiotic metabolism system comprises three
3.1. Pharmacokinetics groups of proteins with distinct and successive functions
Drug absorption, distribution, metabolism, and excre- (28). The first group involves drug functionalization and
tion (ADME) are influenced by circadian systems consists of the microsomal cytochrome P superfamily of
(Fig. 2). Drug concentrations in the blood and the target enzymes, which have oxidase, reductase, or hydroxylase
tissue are regulated by these processes, which can be activities. Many cytochrome P450 genes exhibit circa-
used to determine the pharmacological effects of drugs. dian expression profiles in mice and rats (4, 29 – 31).
Absorption of orally administered drugs depends on The second group involves drug conjugation and consists
several factors such as blood flow, pH, and motility or of conjugating enzymes such as sulfotransferase, gluta-
the emptying level of the gastrointestinal tract. Many thione-S-transferase, N-acetyltransferase, and gluc-
 Chrono-pharmacology 323

uronotransferase. Conjugation helps to make lipophilic shown circadian changes in their expression and func-
compounds hydrophilic enough to subsequently facilitate tions in rodents (46, 47).
their excretion. For example, diurnal variation in hepatic In the central nervous system, many receptors
glutathione-S-transferase, a conjugation reaction enzyme, including adrenergic, GABAergic, serotonergic, cholin-
shows high activity during the light period in mice ergic, dopaminergic, and opiate receptors have shown
(31, 32). The third group contains ATP-binding cassette daily expression rhythms under light–dark or constant
transporters like multi-drug resistance-associated pro- darkness conditions in rodents (48, 49). For enzymes,
teins and P-glycoprotein, which facilitate the transport of the level of monoamine oxidase A, which metabolizes
xenobiotics from outside the cell. The daily rhythms of catecholamines and serotonin, is regulated by the circa-
the gene expression of ATP-binding cassette transporters dian clock system in mice and is the target molecule
were recently reported in mice and rats (24, 25, 33, 34). of antidepressants that inhibit this activity (50). GSK3b
The circadian clock system plays a key role in changes is a target enzyme for lithium that exhibits circadian
in drug toxicity by influencing drug metabolism in the rhythms in enzyme activity and gene expression in
liver and intestine and excreting the metabolites via rodents, suggesting that the chrono-pharmacological
bile and urine. It is known that biliary excretion of bile aspects of lithium should be considered (51). Serotonin
acids, lipids, and xenobiotics follows a circadian rhythm, shows circadian rhythmicity in several brain regions,
with maximum excretion during the dark period in rats including the SCN, pineal gland, and striatum; and it
(35, 36). Bile acid synthesis involves cholesterol-7a- peaks during the light–dark transition but persists under
hydroxylase, a rate-limiting enzyme that converts choles- constant darkness in mice (52 – 54). The RNA expres-
terol into bile acids, whose rhythmic expression is sion levels of the serotonin transporter and its uptake
regulated directly by the transcriptional repressor REV- activity in the mouse midbrain are significantly higher
ERBa in rodents (37 – 39). Drug excretion is influenced in the dark phase than in the light phase (55 – 57).
by kidney functions such as renal blood flow, glomerular These papers strongly suggest the importance of the
filtration rate, and urine volume. Renal blood flow time-dependent effect of antidepressants. Overall, in
exhibits a significant circadian rhythm: it shows a peak addition to drug formulations and routes of administra-
during the active phase, which is twice the level of the tion, the effect of circadian rhythms should be taken into
peak seen during the resting phase in human and rats account when treating a disease with drugs.
(40, 41). Circadian oscillations in glomerular filtration
rate are apparently synchronized with those of renal 4. Chrono-pharmacology: drug input to the circadian
blood flow and systemic hemodynamics, with a 50% clock
change at the day-night transition (42). The day-night
differences in the urinary excretion of some drugs have 4.1. Neuropharmacology
already been examined in rodents (43 – 45), but the The SCN receives both environmental cues, such as
detailed mechanisms of ADME in relation to the circa- the light–dark cycle, and additional information from
dian system are not fully understood. Taking altogether, other brain areas. Exogenous melatonin and ramelteon
we should consider how the circadian clock system (Rozerem; Takeda Pharmaceuticals, Osaka) are notable
affects drug pharmacology. for their effects on the circadian rhythm of the SCN,
and they function as non-photic entrainers which phase-
3.2. Pharmacodynamics advance SCN circadian rhythms when injected in the
Circadian systems not only affect ADME, but also middle of the active phase in mice (58, 59). Similarly,
regulate drug-targeted receptors, drug-targeted trans­ benzodiazepines also entrain the circadian rhythm of
porters/enzymes, drug-targeted intracellular signaling the SCN when injected late at night (60). In hamsters,
systems, and drug-targeted gene transcription. Gene serotonin 1a/7–receptor agonists phase-advance the
array experiments using mice with mutations or with a circadian locomotor activity rhythm by reducing Per1
disrupted circadian clock system have provided new and Per2 gene expression in the SCN (61). Lithium
discoveries demonstrating the pivotal role of the mole­ lengthens the locomotor activity rhythm in rodents by
cular clocks in target function and drug efficacy. For inhibiting GSK3b in the SCN (51). General anesthesia
example, it is recommended to take statin drugs (inhibi- also affects circadian rhythms; some types of anesthesia
tors of HMG-CoA reductase) in the evening because phase shift, while others reduce the rhythmic amplitude
HMG-CoA reductase is most active at this time in of clock gene expression in mice (62). Taken together,
humans. Circadian mechanisms also play critical roles in many central nervous system drugs are able to modulate
cancer and chemotherapeutics, and cell cycle-related circadian rhythm through their target receptors and
genes and enzymes including Wee1, P53, and P21 have enzymes (Fig. 3).
324 Y Tahara and S Shibata

Fig. 3.  Framework of the aspect of chrono-pharmacology: drug input to the circadian clock. Several studies have tried to seek
drugs that affect the circadian system by measuring behavioral changes in vivo or clock gene expression changes in vitro. In both
conditions, phase, period, and amplitude are the important factors for considering the effect of drugs on the circadian system.
Representative drugs we discussed in this review are shown on the left side.

4.2. Small molecules (ERK), KN-62 (CaMKII), KT5823 (PKG), and

As the molecular composition of the core oscillator is SB431542 (ALK) attenuate phase shifts (69 – 74).
largely understood, we are interested in understanding Inducer of cellular c-AMP, phosphodiesterase inhibitor
clock modification by small molecules (Fig. 3). This (rolipram), and secondary inducer of cAMP cause a
strategy can yield a new understanding of basic clock phase delay and enhance amplitude (68). Agonists of
biology and will be useful for developing putative thera- Rev-erba or Rev-erbb reduce amplitude (75, 76), whereas
peutic agents for clock-associated diseases. In several some compounds enhance amplitude while shortening
studies, reporter assays have involved stable cell lines the period (68). Thus, by chemical biology screening
expressing either luciferase alone from an exogenous or targeted ligand development, it will be beneficial to
Bmal1 promoter (63 – 67) or PER2::LUCIFERASE find small molecules capable of manipulating the clock.
fusion proteins from the endogenous Per2 promotor (68), Other approaches are also available. Many medicinal
corresponding to mRNA or protein rhythm, respectively. drugs, including Chinese traditional medicines, are used
Bioluminescence was monitored for several days to to treat diseases. However, the effects of these drugs on
determine the oscillation period and amplitude. As light the circadian system are not known. As we describe in
pulses cause phase delay and phase advance when the next section, we have the opportunity to find func-
light stimuli are provided in the early evening and late at tional foods and nutrients.
night, respectively, small molecules can phase-shift the
oscillation rhythm depending on the time of their appli- 5. Chrono-nutrition: circadian regulation of physio-
cation. These screening methods enabled us to find small logical functions
molecules capable of modifying the core loop of the
clock, as well as the input and output pathways of the 5.1. Digestion and absorption
core clock. Several studies have demonstrated the Digestion and absorption in the stomach and intestines
feasibility of developing a “clock drug” to alter clock follow circadian rhythms in mammals, and these rhythms
gene expression and rhythms (63 – 65, 68). are regulated by rhythmically expressed clock genes in
To date, around 200,000 compounds have already the gut as well as by daily food intake (15, 18). For
been screened and characterized as period lengthening chrono-nutrition, we can consider digestion and absorp-
or shortening; phase delaying, phase advancing, or phase tion (Fig. 4). The circadian rhythms of expression clock
attenuating; and amplitude enhancing or amplitude genes in the digestive organs have already been carefully
reducing. Compounds with period-lengthening activity investigated. Interestingly, the data suggest that the
include casein kinase 1 inhibitor, p38 inhibitor, JNK in- phases of the rhythms in clock gene expression differ
hibitor, and PP2A inhibitor, while compounds exhibiting among the cranio-caudal axes of the gut in mice (77).
period-shortening activity include DNA topoisomerase II The phase in the upper gut appears to be phase-advanced
inhibitor, PKC agonist, CDK inhibitor, and GSK3b compared with that in the lower gut, suggesting that
inhibitor. Various kinase inhibitors including U0126 the upper gut is entrained faster than the lower gut by
 Chrono-pharmacology 325

Fig. 4.  Framework of the aspect of chrono-nutrition: circadian regulation of nutrition functions. Food/nutrition digestion,
absorption, and metabolism are influenced by the circadian system. In addition, motility and proliferation of epithelial cells in
digestive tubes including the colon have circadian rhythms.

varying the speed of food and nutrition delivery. Micro- and Glut5 have clear circadian oscillations in their
array analysis of the distal colon revealed that 3.7% of expression (83, 84) and are regulated by clock genes
all genes have a circadian pattern of gene expression through E-box activity (85). Furthermore, Sglt1 is regu-
and that these genes are related to cell signaling, differ- lated by PER1 activity independent of the E-box (86).
entiation, proliferation, and death in mice (78). The Sglt1 and Pept1 were phase-entrained by a scheduled
scheduled-feeding paradigm in the daytime for nocturnal feeding experiment. Therefore, these transporters are
mice showed a phase shift in the rhythms of clock gene directly regulated by feeding conditions (87). In Clock
expression in the gastrointestinal tract (79). Therefore, mutant mice, peptide transportation was reduced, but
nutrient signaling can affect gut circadian systems. lipid absorption was high (21). In contrast, Nocturnin
Colonic motility in humans is also known to have a (i.e., clock-regulated deadenylase)-knockout mice showed
circadian rhythm. A study showed frequent movement of that lipid absorption was reduced because of reduced
the colon during the day and minimal movement during chylomicron transit (88). Expression of the sodium pump
the night (80). Mice have a similar day–night rhythm (Atpa1a), sodium channel (gEnac), sodium transporters
in colonic motility, which is regulated by clock genes (Dra, Ae1, and Nhe3), and the Na+/H+ exchanger regula-
and neuronal nitric oxide synthase activity (80). Stool tory factor (Nherf1) in rat colonic mucosa showed circa-
weight, the colonic contractile response of acetylcholine dian variations, suggesting that NaCl absorption in the
(measured by colonic organ culture), and intracolonic colon was under circadian regulation (89). The drug
pressure (measured by the telemetry system in the wild transporters Mdr1, Mct1, Mrp2, Pept1, and Bcrp also
type) all showed clear circadian rhythms; however, these showed circadian expression in rat jejunal mucosa (26).
rhythms were disrupted in Per1 and Per2 double- Taken together, these data show that many important
knockout mice or in nNOS-knockout mice. The intestinal transporters are under circadian regulation, and circadian
digestive enzyme sucrase also follows a circadian change disruption leads to abnormal absorption.
in activity, peaking before feeding time (81). Therefore,
the digestive system undergoes circadian changes in both 5.2. Intestinal epithelium
rodents and humans. Self-renewing epithelial cells arise from the stem
Several studies have reported circadian variations in cells located in the lower part of the intestinal crypts.
the intestinal absorption of glucose, peptides, lipids, and Measurement of thymidine or Brdu incorporation has
drugs by several transporters. Isolated rat small intestine shown that the circadian rhythm mediates the prolifera-
showed increased absorption of glucose and water at tion of the intestinal epithelium in both humans and
nighttime compared with daytime (82). Sodium/glucose rodents (90 – 93). This rhythm persisted under fasting
cotransporter 1 (Sglt1), glucose transporter 2 (Glut2), in mice (94), and expression was dramatically enhanced
326 Y Tahara and S Shibata

by re-feeding (93). Thus, circadian clock disruption causes energy metabo-

The detailed mechanism of the circadian control of lism dysfunction, suggesting that the circadian system
cell proliferation remains largely unknown, but three tightly regulates metabolic functions.
mechanisms have been proposed. First, wee1, a negative Important metabolic factors like AMPK, Sirt1, Ppara,
regulator of the G2/M transition, is likely a clock- and Pgc1a follow circadian rhythms in their activity
controlled gene in colonic epithelial cells because its and act as important regulators of core circadian
promoter contains an E-box (46), and wee1 gene expres- mechanisms. AMPK, which is a nutrient sensor in
sion exhibits circadian changes (77, 95). Second, the peripheral tissues, acts in the destabilization of CRY
proliferation level is controlled by extrinsic luminal sig- protein in the core of the circadian system (103). Sirt1,
nals, neural output signals (glucocorticoids), gastric an anti-aging gene regulated by nicotinamide adenine
hormones (gastrin and neurotensin), and growth factors dinucleotide (NAD+), regulates the histone acetyltrans-
(EGF) because all show a circadian pattern (96). Third, ferase activity of CLOCK protein (104, 105) and pro-
rhythmic food intake may control daily rhythm in the motes deacetylation and degradation of PER2 (106).
cell cycle through the enteric nervous system. Ppara, which is a nuclear receptor for lipid metabolism
in the liver, binds with PER2 (107) and promotes Bmal1
5.3. Metabolism and energy expenditure expression through PPRE in the promoter of Bmal1 (108).
The circadian system in mammals tightly regulates Pgc1a, a transcriptional coactivator for the regulation of
energy metabolism. This seems reasonable given that energy metabolism, is also involved in circadian regula-
clock gene mutations or deletions are reported to lead to tion and promotes the expression of Bmal1 and Rev-erba
dysfunctions in energy metabolism (3). Clock mutant through the RORE site (109). Thus, the core metabolic
mice show an attenuated feeding rhythm and obesity genes are tightly related to the clock systems, and their
when fed a regular diet or high-fat diet (HFD) (97). activities undergo circadian changes.
Per2−/− mice showed disrupted feeding rhythms and
obesity due to disrupted glucocorticoid rhythms when 6. Chrono-nutrition: food input to the circadian clocks
fed a HFD (98). Per2−/− mice also experienced disrup-
tions in the circadian rhythm of alpha MSH, which 6.1. Food anticipatory activity (FAA)
regulates feeding behavior in the hypothalamus. Rev-erba Daily scheduled feedings, restricted to only a few
and Rev-erbb, which play roles in the functioning of hours throughout the day, induce time-specific arousal
nuclear receptors and core clock genes, were reported in rodents (i.e., FAA) (Fig. 5). FAA appears roughly
to regulate lipid metabolism (99, 100). Antagonists of 2 – 3 h before feeding time and is thought to indicate
Rev-erbs can improve or prevent HFD-induced obesity that mice are anticipating food at the scheduled time.
and circadian disruption in mice (76). Bmal1-knockout Therefore, it is believed that mice can learn and remem-
mice showed obesity and lower insulin secretion com- ber the timing of regular feedings through their internal,
pared with wild-type mice (101). Adipocyte-specific food-entrainable oscillator (FEO). In addition to FAA,
deletion of Bmal1 led to obesity, and interestingly, a shift food can entrain clock-gene expression rhythms in
in food intake timing from nocturnal to diurnal, which many areas of the brain and in almost all peripheral
was caused by a change in the levels of circulating tissues, but not in the SCN. After cloning core clock
polyunsaturated fatty acids and nonesterified polyunsatu- genes in the 1990s, several studies investigated the
rated fatty acids in the hypothalamic neurons (102). entrainment of peripheral clocks by using scheduled

Fig. 5.  Framework of the aspect of chrono-nutrition: food/nutrition input to the circadian clocks. Timing, components, and
amount of food/nutrition could be important factors to stimulate the circadian system in mammals. Scheduled feeding–induced
entrainment of the circadian system can be observed at the behavioral and molecular levels.
 Chrono-pharmacology 327

feeding experiments. Our group showed that Per1, Per2, with 22-h periodic feedings, but not in Cry2−/− (long-
D-site-binding protein, and cholesterol 7 alpha-hydroxy- period mutant) or wild-type mice. Taken together, mice
lase mRNA expression rhythms in the liver underwent may use the circadian system to remember feeding times
phase shifting and entrainment with daytime feedings in and induce FAA.
mice (110). However, the Per1 and Per2 expression To understand the FEO mechanism, we have to
rhythms in the SCN did not undergo phase shifting with consider the motivation of food intake during FAA and
scheduled feedings. Similar results were reported in the before feeding. Ghrelin secreted from the stomach acts
field of circadian research at the same time. Stokkan et as a circulating hormone to relay the hunger state to the
al. (111) reported that the liver clock phase was initially hypothalamus before food intake. Ghrelin-receptor–
shifted by 10 h within 2 d. Damiola et al. (112) reported knockout mice showed significantly reduced FAA for-
that this food-induced phase resetting occurs faster in mation during a daytime-scheduled feeding experiment
the liver than in the kidney, heart, or pancreas. In (124, 125). However, normal FAA formation in pre-
essence, food appears to be a strong entrainable factor proghrelin-knockout mice has been reported (126).
with respect to mammalian clocks. In addition, this Orexin (hypocretin), which is an important neuropeptide
entrainment will fix the timing of food digestion and for promoting wakefulness and locomotor activity, was
metabolism by controlling clock-regulated output genes reported to be involved in food anticipation. Orexin
in the peripheral tissues. neuron–ablated mice showed a severe deficit in FAA
To investigate the location or mechanism of the FEO, increase with scheduled feedings (127, 128). In orexin
many researchers have tried to diminish FAA in mice by neurons in the lateral hypothalamus, fos expression
using knockout, mutant, or specific brain-part–lesioned exhibits rhythms that shift in response to scheduled
mice. In lesion studies, the dorsomedial hypothalamus feedings. Therefore, the orexin neurons and lateral
(DMH), which plays a role in regulating eating behavior, hypothalamus are involved in the FEO. Melanocortin-3
is reported to be one of the possible locations of the FEO. receptor–deficient mice also showed decreased FAA
Several studies have demonstrated that DMH-lesioned formation (129), reduced food intake, and melanocortin-3–
mice and rats showed a significant reduction in FAA receptor expression in the hypothalamus. More recently,
formation (113 – 115). However, the ability to induce Sirt1, the NAD-dependent deacetylase, was reported to
FAA was still present in DMH-lesioned mice (116, 117). be involved in the FEO (130). Researchers have reported
The decisive data provided by Acosta-Galvan et al. (117) that brain-specific Sirt1-knockout show decreased FAA
indicate that DMH-lesioned mice have reduced FAA, in the daytime-scheduled feeding paradigm, and Sirt1
whereas both DMH- and SCN-lesioned mice have was shown to upregulate the expression of the orexin
increased FAA. This result suggests that the DMH is type 2 receptor in the hypothalamus in response to sched-
part of the FEO but not a prerequisite for the induction uled feedings. Taken together, hunger, or the motivation
of FAA. Furthermore, the data suggest that the SCN for food intake, appears to mediate the mechanism of
inhibits FEO entrainment because the SCN is entrained FEO formation in hypothalamic nuclei.
by light–dark information through the retina. In view of
these results, the FEO is thought to be a large network 6.2. Food timing
structure in the brain. Therefore, it is difficult to ascertain A recent chrono-nutritional study provided some
the location of the new oscillator, as with the SCN. insight into the optimal timing of food intake for main-
Circadian clock genes are thought to be involved in taining body weight and health (Fig. 5). Although it has
the FEO mechanism. However, several controversial always been speculated that eating late at night carries a
papers have been published on the subject. Per2 mutant/ high risk of developing obesity, there is minimal evi-
knockout mice and Bmal1-knockout mice were reported dence to support this hypothesis. Recently, several clini-
to exhibit normal FAA or reduced FAA in different cal studies have demonstrated this phenomenon. Hsieh et
studies performed in different laboratories (118 – 121). al. (131) showed that subjects with short sleep duration
Recently, Mieda and Sakurai (122) showed that nervous (< 5 h) had significantly higher risk for developing
system-specific Bmal1 deletion caused a reduction in obesity, diabetes, and poor sleep and eating late dinners
the entrainment ability of the scheduled-feeding para- than subjects with a longer sleep duration (> 5 h). Baron
digm, suggesting that Bmal1 is an essential component et al. (132) reported that late sleepers (midpoint of sleep
of the FEO. Additionally, Takasu et al. (123) demon- > 5:30 AM) consumed more calories at dinner and after
strated that clock-gene mutant or knockout mice have 8:00 PM and were more at risk for obesity than normal
different abilities for adapting to different periodic sleepers (midpoint of sleep < 5:30). Clinical studies in a
feeding paradigms (T-cycle experiment). In fact, FAA laboratory setting showed that adults with insufficient
can be induced in Cry1−/− mice (short-period mutant) sleep for 5 consecutive days experienced increased total
328 Y Tahara and S Shibata

daily energy expenditure, but the energy intake after effective at resetting the clock phase if the dinner time
dinner increased and exceeded the energy needed to is late at night. Moreover, such a phase change may
maintain an energy balance (133). In addition, humans cause late-night dinner-induced obesity.
and rats selected foods with a higher fat composition at High-fat food intake leading to obesity induced a long
dinner time than at breakfast time (134, 135), suggesting free-running period of locomotor activity rhythms and
a nutritional preference that leads to obesity with late- decreased the amplitude of clock or clock-controlled
night feeding. These findings indicate that late dinners gene expression rhythms in hepatic and adipose tissue
carry the risk of obesity in humans. (144). However, two recent studies have shown promis-
The same findings were found in rodents. Scheduled ing results which suggest that eating according to the
food intake (e.g., HFD) during only light periods caused same daily schedule can diminish HFD-induced obesity.
higher weight gain than food ingested at night (136). Scheduled high-fat feedings for 8 h during the dark
Mice maintained under dim lighting conditions at night- period (145) or for 4 h during the light period (146)
time (i.e., light at night) showed increased food intake without calorie restriction prevented obesity. These
during the daytime. As a result, their body weight studies suggest that regulating the timing of food intake
increased compared with mice maintained under normal can improve the amplitude of the clock and clock-
light–dark conditions (137). Consumption of a HFD controlled metabolic-related gene expression rhythms,
at the end of the dark period induced increased weight nutrient utilization, energy expenditure, and insulin
gain, adiposity, glucose intolerance, hyperinsulinemia, sensitivity. Similarly, our group demonstrated that
hypertriglyceridemia, and hyperleptinemia (138, 139). scheduled access to food during the active phase led to
Similarly, mice fed breakfast only showed body weight a recovery from disrupted locomotor-activity rhythms
gain, hyperinsulinemia, hyperleptinemia, and decreased and disrupted Per2 expression rhythms in db/db mice,
expression of b-oxidation-related genes in adipose and known causes of severe obesity, type 2 diabetes, and
hepatic tissue compared with mice fed a bigger breakfast low-amplitude cycles of clock genes (147).
and a smaller dinner (140). Therefore, the timing of food For night shift work–induced obesity in rats and mice,
intake is an important factor for maintaining appropriate scheduled food access proved helpful for preventing
body weight. However, the reason for this phenomenon obesity. Extensive epidemiological studies of rotating
is still unknown. night shift work revealed that nurses who worked for
One reason may be the phases of clock gene expres- longer periods during their shift carried a higher risk of
sion that change with the timing of food intake. Late- type 2 diabetes than nurses who worked shorter shifts
night dinners may cause changes in clock gene expres- (148). Karatsoreos et al. (149) reported that a 20-h
sion in the peripheral tissues. Our group reported that light-dark cycle in mice induced obesity and irregular
food volume and starvation intervals are important release of metabolic hormones, as well as decreased
factors for determining the peripheral clock phase (141, dendritic length in the prelimbic prefrontal cortex. To
142). A feeding schedule of 2 meals per day in mice avoid these effects, scheduled feedings during the dark
induced only one peak in the rhythm of clock gene period with restricted arousal for 8 h during the light
expression in peripheral tissues (141, 143). On the other period prevented obesity induced ad libitum (150).
hand, a feeding schedule of 2 – 3 meals per day in mice, Similarly, scheduled feeding of night shift work mice
with food intake following a longer fasting interval, was during the normal dark phase was shown to prevent
more effective at entraining the peripheral clock phase dyssynchrony of rhythmically expressed hepatic genes
than other feeding schedules. In the study by Kuroda in microarray analysis (151). Therefore, meal timing is
et al. (142), food timing mimicked human eating pat- important for preventing obesity.
terns. Food at Zeitgeber time (ZT, ZT 0 = lights on) 12 In addition to obesity, rotating night shift work carries
was set to breakfast, food at ZT 18 (middle of the dark a higher risk of developing cancer. According to a large-
period) was set to lunch, food at ZT 1 or ZT 4 was set to scale prospective cohort in Japan, there was a significant
dinner, and food at ZT 4 was set to late dinner. In fact, increase in the risk of prostate cancer (152). WHO’s
mice fed at ZT 12 (breakfast), ZT 18 (lunch), and ZT 1 International Agency for Research on Cancer determined
(dinner) were entrained by food at ZT 12, because this in 2007 that rotating night shift work is a probable
feeding was 11 h after the last meal (ZT 1), whereas the factor in cancer. In mice, chronic jet lag also accelerated
other meal came 6 or 7 h later. However, mice fed at malignant growth (153). Intriguingly, on a similar
ZT 12, ZT 18, and ZT 4 (late dinner) were entrained by manner related to obesity, scheduled feeding was effec-
food at ZT 4 (late dinner) because this feeding came tive at reducing the speed of cancer growth, especially
10 h after the last meal at ZT 18, whereas food at ZT  when food was given during the light period in mice
12 came 8 h later. This suggests that dinner is more (154). Scheduled feedings can change the amplitude of
 Chrono-pharmacology 329

circadian clock gene expression rhythms and tumor signal for food entrainment in the liver. However, this
genes, such as Hspa8, Cirbp, and Ccna2. Therefore, the pathway is not necessary to demonstrate FAA or entrain
timing of food intake can improve not only obesity, but peripheral clocks. Because streptozotocin induced
also cancer growth, by changing the strength of circadian pancreatic beta cell destruction, which causes the loss
systems in a chronic jet lag model for mice. Chronic jet of insulin production, it cannot be used to protect against
lag also induced increased mortality in aged mice (155) food-induced FAA or phase shifts in hepatic clock genes
and dysregulation of the inflammatory response by endo- (168, 169). Taken together, insulin signaling is one of
toxemic shock (156) and experimental colitis (157). the most important factors for food entrainment, but the
These phenotypes might be improved by temporal regu- unknown mechanisms of the peripheral FEO remain to
lation of food ingestion. Chrono-pharmacology kinetics be elucidated. Poly (ADP-ribose) polymerase 1 (PARP-
can also be manipulated by the food timings. Matsunaga 1), a NAD+-dependent ADP-ribosyltransferase, is a
et al. (158) investigated whether the level of hepato­ possible factor of food entrainment. PARP-1 binds and
toxicity and mortality after injecting acetaminophen poly(ADP-ribosyl)ates CLOCK, and PARP-1–knockout
in mice had circadian rhythms through CYP2E1 and mice exhibit impaired food entrainment of clock gene
hepatic glutathione activities. In addition, this rhythmic expression rhythms in the liver (170). AMPK, a nutrient
response of acetaminophen could be manipulated by sensor, is another possible factor for food entrainment.
scheduled feeding during the light phase. Similar AMPK is activated by fasting or low glucose levels.
manipulations of food timings on the chrono-pharmaco­ It then phosphorylates and destabilizes CRY1 protein
logy kinetics were reported in the activity of sodium (103). Diet-induced heat production is also a possible
valproate (159) and in the nephrotoxicity of gentamicin factor of food entrainment. Heat stimulation and body
(160). Thus, considering regulation of eating timings temperature cycles are now reported to be entrainable
might be helpful for the drug therapy of diseases. factors of peripheral clock genes (171 – 173). Recent
evidence by Gerber et al. (174) suggests another
6.3. Nutritional signals possible factor; they found through unique screening
Understanding the mechanisms of food entrainment in of transcription factors that the serum response factor
the circadian system will contribute to chrono-nutritional has rhythmic transcriptional activity in humans and
therapy concerning the functionality of food and nutri- rodents. In contrast, the glucocorticoid hormone nega-
tion (Fig. 5). FAA is an index of the FEO, and clock gene tively affects food entrainment in peripheral tissues.
entrainment in peripheral tissues is another good index Adrenalectomized mice showed faster entrainment by
of the FEO. This peripheral entrainment appeared 1 –  food compared with sham-operated mice, and hepato-
2 d after starting the scheduled feedings, whereas FAA cyte-specific glucocorticoid receptor–null mice showed
appeared within 3 – 5 d (115, 161). Therefore, FEO may faster entrainment to restricted feeding than wild-type
be located in the peripheral tissues. In fact, the expres- mice (175). In summary, the mechanisms underlying
sion of many genes, including clock genes in the liver, peripheral clock gene entrainment by food remain a
changed rapidly with daytime re-feeding. In microarray mystery.
analysis of the hepatic genes, Vollmers et al. (162) The next question is what kind of nutrition has the
showed that re-feeding downregulated the CREB- and power to induce entrainment in the circadian clock
FoxO1-targeted genes but upregulated SREBP- and system. Our group focused on the composition of the
ATF6-targeted genes. In addition, Per1 was downregu- standard diet AIN-93M [14% casein, 47% cornstarch,
lated, while Per2 was upregulated by daytime re-feeding. 15% gelatinized cornstarch, 10% sugar, 4% soybean oil,
Similarly, Per2 (161, 163) and Dec1 (163) were upregu- and others (e.g., fiber, vitamins, and minerals)] (176).
lated, while Rev-erba was downregulated by re-feeding We changed the composition of nutrients during a day-
(161). The induction of Per2 expression by food is time scheduled feeding experiment (only 2 d feeding)
regulated by insulin signaling. Balsalobre et al. (164) and checked for phase entrainment in liver rhythm by
showed that multiple signaling pathways, including ex vivo cultured hepatic PER2::LUC bioluminescence.
insulin signaling, can induce Per2 expression. Similarly, The results showed that 100% of the cornstarch or soy-
insulin directly induced Per2 expression in hepatic bean oil could induce a phase shift, but other nutrients
tissue and three-dimensionally cultured hepatocytes could not. In addition, a combination of glucose and
(161, 165, 166). In addition, our recent study demon- casein without oil, vitamins, or fiber could entrain the
strated that rapidly digested starches cause higher blood liver clock phase. A high-salt diet also changed the
glucose and higher insulin secretion and induce a larger peripheral clocks by increasing glucose absorption
phase shift in the rhythms of liver Per2 expression (167). through the upregulated Sglt1 and Glut2 in the jejunum
Therefore, food-induced insulin secretion is an important (177). Similarly, streptozotocin-induced insulin-deficient
330 Y Tahara and S Shibata

mice, which have high blood glucose levels, showed a Transcriptional architecture and chromatin landscape of the
phase-advanced peripheral clock phase (178). In contrast, core circadian clock in mammals. Science. 2012;338:349–354.
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ketogenic diets, accompanied by hypoglycemia, caused
cells. Nature. 2011;469:498–503.
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effect was caused by a shortened circadian free-running Bouget FY, et al. Circadian rhythms persist without transcription
period of the SCN and a behavioral phase in the normal in a eukaryote. Nature. 2011;469:554–558.
light–dark cycle. A palatable non-nutritive mash with 10 Wang TA, Yu YV, Govindaiah G, Ye X, Artinian L, Coleman TP,
restricted access induced FAA (180). A palatable snack et al. Circadian rhythm of redox state regulates excitability in
(chocolate) in the daytime also elicited FAA and c-Fos suprachiasmatic nucleus neurons. Science. 2012;337:839–842.
expression in the corticolimbic area (181), and this 11 Mistlberger RE. Neurobiology of food anticipatory circadian
rhythms. Physiol Behav. 2011;104:535–545.
entrainment is thought to be mediated by ghrelin (182).
12 Shibata S, Tahara Y, Hirao A. The adjustment and manipulation
Scheduled access to high-fat chow ad libitum caused of biological rhythms by light, nutrition, and abused drugs.
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can induce the FEO. Other nutritional ingredients such as metabolic syndrome and obesity. Adv Drug Deliv Rev. 2010;
caffeine can lead to considerable changes in the circadian 62:967–978.
system. Caffeine was reported to lengthen the circadian 14 Delezie J, Challet E. Interactions between metabolism and
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15 Bron R, Furness JB. Rhythm of digestion: keeping time in the
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terase, which increases cAMP concentrations. Taken 1041–1048.
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Acknowledgments tion of circadian rhythms in the gastrointestinal tract. J Physiol
Pharmacol. 2011;62:139–150.
This work was supported by grants to Y.T. from the Mishima-Kaiun 18 Scheving LA. Biological clocks and the digestive system.
Foundation (2010) and Grants-in-Aid for Young Scientist (Start-up, Gastroenterology. 2000;119:536–549.
25893265), and in part by grants to S.S. in the form of Grants-in-Aid 19 Scheving LA, Russell WE. It’s about time: clock genes unveiled
for Scientific Research from JSPS (23300278, 23659126), from the in the gut. Gastroenterology. 2007;133:1373–1376.
Fuji Foundation for Protein Research (2010, 2012), from the Iijima 20 Pan X, Hussain MM. Diurnal regulation of microsomal
Memorial Foundation for the Promotion of Food Science and triglyceride transfer protein and plasma lipid levels. J Biol
Technology (2011), from KIBANKEISEI (2012) from a matching Chem. 2007;282:24707–24719.
fund subsidy from MEXT, Japan, and from the Program for Promo- 21 Pan X, Hussain MM. Clock is important for food and circadian
tion of Basic and Applied Researchers for Innovations in Bio-oriented regulation of macronutrient absorption in mice. J Lipid Res.
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