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The role of the circadian clock system in nutrition and metabolism

Published online by Cambridge University Press:  08 June 2012

Felino R. Cagampang*
Affiliation:
Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, MP887 Southampton General Hospital, Tremona Road, SouthamptonSO16 6YD, UK
Kimberley D. Bruce
Affiliation:
Institute of Developmental Sciences, Faculty of Medicine, University of Southampton, MP887 Southampton General Hospital, Tremona Road, SouthamptonSO16 6YD, UK
*
*Corresponding author: Dr F. R. Cagampang, email f.cagampang@soton.ac.uk
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Abstract

Mammals have an endogenous timing system in the suprachiasmatic nuclei (SCN) of the hypothalamic region of the brain. This internal clock system is composed of an intracellular feedback loop that drives the expression of molecular components and their constitutive protein products to oscillate over a period of about 24 h (hence the term ‘circadian’). These circadian oscillations bring about rhythmic changes in downstream molecular pathways and physiological processes such as those involved in nutrition and metabolism. It is now emerging that the molecular components of the clock system are also found within the cells of peripheral tissues, including the gastrointestinal tract, liver and pancreas. The present review examines their role in regulating nutritional and metabolic processes. In turn, metabolic status and feeding cycles are able to feed back onto the circadian clock in the SCN and in peripheral tissues. This feedback mechanism maintains the integrity and temporal coordination between various components of the circadian clock system. Thus, alterations in environmental cues could disrupt normal clock function, which may have profound effects on the health and well-being of an individual.

Type
Horizons in Nutritional Science
Copyright
Copyright © The Authors 2012

Most mammals have evolved so that they are able to predict the 24 h day–night cycle governing their daily activities. Key to this is the development of an internal body clock that is entrained to external time cues, thus ensuring that physiological processes are carried out at the optimum time of the day or night(Reference Panda and Hogenesch1, Reference Roenneberg, Kumar and Merrow2). This endogenous clock system runs on a near-24 h period and is termed ‘circadian’ from the Latin word circa and diem, which translates as ‘about a day’. Disruption in the integrity and temporal coordination of this clock system can lead to hormonal imbalances, sleep disorders, susceptibility to cancer and other disease states, as well as to a reduction in lifespan(Reference Rana and Mahmood3Reference Froy7).

Although malnutrition is still a major public health concern in developing countries, there has also been an escalation in the global epidemic of obesity coined as ‘globesity’ by the WHO, particularly in many industrialised societies. Serious health problems, including the development of diabetes mellitus, CVD, hypertension, stroke and certain types of cancers, can arise as a consequence of being overweight or obese, and this could overwhelm the healthcare infrastructure of societies. Key to how we prevent obesity is to maintain energy homeostasis, i.e. the balance in energy intake and energy expenditure. Major components of energy homeostasis, including the sleep–wake cycle, feeding behaviour, thermoregulation and metabolism, exhibit circadian rhythms which are controlled and coordinated by the circadian clock system(Reference Jung-Hynes, Reiter and Ahmad8Reference Ramsey and Bass10). Conversely, external stimuli such as light, temperature, and the timing and type of nutrient intake can also influence clock function. Thus, further investigation into the relationship between the circadian clock system and nutrition will reveal mechanisms involved in energy homeostasis and the pathogenesis of obesity. The present review summarises recent findings on the importance of the endogenous circadian clock system in the regulation of nutritional and metabolic processes.

Molecular aspect of the circadian clock system

Daily oscillations in the gene and protein components of the endogenous molecular clock network mediate circadian rhythms in both physiological and metabolic outputs. These oscillations are generated through a series of positive and negative feedback loops and involve a number of genes collectively known as ‘clock’ genes and their constitutive proteins (see Fig. 1). These genes include the brain and muscle ARNT-like protein 1 (Bmal1; also known as Mop3 or Arntl), circadian locomotor output cycles kaput (Clock), Period 1 (Per1), Period 2 (Per2), Period 3 (Per3), cryptochrome 1 (Cry1) and cryptochrome 2 (Cry2)(Reference Dibner, Schibler and Albrecht11Reference Lowrey and Takahashi13). The positive drivers to this system are the two basic helix–loop–helix Period–Arnt–Single-minded domain-containing transcription factors CLOCK and BMAL1, which form a heterodimer complex. CLOCK is a histone acetyltransferase, and its activity is stimulated following heterodimerisation with BMAL1(Reference Doi, Hirayama and Sassone-Corsi14). The CLOCK–BMAL1 dimer binds to the E-box elements in the Per1, Per2, Per3, Cry1 and Cry2 genes and activates their transcription, facilitated by histone acetylation. Following translation, PER and CRY proteins form complexes and translocate back to the nucleus where they then exert a negative feedback effect on the transcriptional activity of the CLOCK–BMAL1 heterodimer, thus inhibiting their expression and completing the feedback loop. In this feedback loop, the protein kinase casein kinase 1 epsilon (CK1ɛ) has been shown to phosphorylate the PER proteins that have accumulated in the cytoplasm. As the phosphorylated forms of PER become unstable, they are then degraded by ubiquitinylation. On the other hand, the accumulation of CRY proteins in the cytoplasm promotes the formation of stable CK1ɛ–PER–CRY complexes, and subsequently enters the nucleus(Reference Eide, Woolf and Kang15). This series of events allows the clock genes to exhibit an oscillatory pattern of expression over a period of about 24 h. Typically, CLOCK and BMAL1 dimerise in the early morning. Subsequently, the transcription of Per and Cry peak at noon, to inhibit the activity of CLOCK–BMAL1 complexes leading to decreased expression of Per and Cry. Eventually, levels of PER and CRY will become too low to maintain this negative feedback, and CLOCK and BMAL1 will begin to complex again, reinitiating the cycle(Reference Harms, Kivimae and Young16). Bmal1 expression is also negatively regulated by the transcription factor reverse erythroblastosis virus α (REV-ERBα)(Reference Preitner, Damiola and Lopez-Molina17) and positively regulated by retinoic acid receptor-related orphan receptor α (RORα)(Reference Sato, Panda and Miraglia18) via the RORα response element in the Bmal1 promoter(Reference Ueda, Hayashi and Chen19). These interlocking positive and negative transcriptional–translational feedback loops regulate numerous downstream clock-controlled genes with key roles in metabolic processes, which are central to how the clock systems generate circadian rhythms in nutrition and metabolism.

Fig. 1 The core mechanism of the circadian clock in the suprachiasmatic nuclei and peripheral tissues. The cellular oscillator is composed of a positive limb (circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1)) and a negative limb (cryptochrome (CRY) and period (PER)). CLOCK and BMAL1 dimerise in the cytoplasm and translocate to the nucleus. The CLOCK–BMAL1 heterodimer then binds to enhancer (E-box) sequences located in the promoter region of the Per and Cry genes, as well as other clock-controlled genes (CCG) activating their transcription. After translation, PER and CRY undergo nuclear translocation and inhibit CLOCK–BMAL1, resulting in decreased transcription of their own genes. Casein kinase 1 epsilon (CK1ɛ) periodically binds to and phosphorylates the PER proteins, which form heterodimers with each other and interact with CRY. The phosphorylation of the PER proteins prevents nuclear entry and also increases their ubiquitination, which leads to degradation. However, this can be overcome when the PER–CK1ɛ protein complex is bound to CRY. The autoregulatory transcription–translation loop comprising CLOCK–BMAL1 and PER–CRY constitutes the core clock and generates 24 h rhythms of gene expression. Retinoic acid receptor-related orphan receptor α (RORα) stimulates and reverse erythroblastosis virus α (REV-ERBα) inhibits Bmal1 transcription.

The mammalian circadian clock system

The circadian clock system in mammals consists of a master pacemaker clock and clock gene networks in peripheral tissues (see Fig. 2). The master pacemaker clock, also known as the central clock, is found in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus of the brain, adjacent to the optic chiasm. The SCN clock is composed of multiple, single-cell circadian oscillators numbering between 10 000–20 000 neurons, which, when synchronised, generate coordinated circadian outputs that orchestrate overt rhythms(Reference Kalsbeek, Palm and La Fleur20Reference Mohawk and Takahashi23). The critical role of the SCN was first recognised when circadian rhythms of activity, drinking and feeding were abolished by electrolytic lesions of this area in the rat brain(Reference Stephan and Nunez24). SCN grafts on SCN-ablated animals have been shown to restore circadian locomotor rhythms(Reference Silver, LeSauter and Tresco25, Reference Aguilar-Roblero, Morin and Moore26). Circadian rhythms generated by the SCN clock are reset daily by daylight, ensuring that the central clock is kept entrained to the external day–night cycle. In the absence of such daylight cues, as when an individual is kept in total darkness for an extended period of time, rhythms will eventually ‘free-run’ and drift across the entire day(Reference Maury, Ramsey and Bass27). As an example, mammals that are exposed to a continuous lighting environment, such as reindeer living above the Arctic Circle, lack circadian oscillations of clock components(Reference Stokkan, van Oort and Tyler28). Thus, daylight is a potent ‘zeitgeber’ (German for ‘time-givers’), which is able to synchronise or ‘entrain’ the clock system in the SCN to the day–night cycle. The position of the SCN, which is adjacent to the optic chiasm, makes it ideal to receive visual input for light entrainment via the retinohypothalamic tract(Reference Albrecht and Eichele29). Light is detected by a particular type of retinal ganglion cell containing the photopigment melanopsin(Reference Peirson and Foster30). These photic inputs are then transduced to the SCN neurons through a number of neurotransmitters, including glutamate and pituitary adenylate cyclase-activating peptide, which are thought to transcriptionally induce Per1 expression through ion channel activation and the intracellular kinase–cAMP response element-binding (CREB) cascade(Reference Reppert and Weaver31).

Fig. 2 The mammalian circadian clock system and its link to nutrition and metabolism. Photic signals received by retinal cells in the eyes are conveyed to the master clock in the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract (RHT). The clock system in the SCN then conveys this zeitgeber to peripheral clock systems in the liver, pancreas and gastrointestinal (GI) tract via humoral and neuronal signals, which in turn regulate rhythms in nutritional and metabolic processes. Feeding rhythms, including food anticipatory activities, are also regulated by the master SCN clock. Nutritional zeitgebers such as malnutrition (over- or undernutrition) and restricted mealtimes can also entrain the clock systems and rhythmic processes in peripheral tissues, as well as feeding rhythms via a food-entrainable oscillator in non-SCN regions of the brain. DMH, dorsal medial nucleus of hypothalamus.

Similar clock systems are found within the cells in non-SCN neurons and in peripheral tissues, including the heart(Reference Peirson, Butler and Duffield32, Reference Young, Razeghi and Taegtmeyer33), liver(Reference Peirson, Butler and Duffield32, Reference Davidson, Castanon-Cervantes and Stephan34), gastrointestinal (GI) tract(Reference Konturek, Brzozowski and Konturek35, Reference Hoogerwerf, Hellmich and Cornelissen36) and pancreas(Reference Marcheva, Ramsey and Buhr37, Reference Sadacca, Lamia and deLemos38), in both humans and animals. However, the rhythmicity of clock gene expression in peripheral tissues can be up to 4 h out of phase with the rhythms found in the SCN(Reference Peirson, Butler and Duffield32, Reference Lee, Etchegaray and Cagampang39, Reference Yoo, Yamazaki and Lowrey40). This is due to the hierarchical organisation of the central clock, which sends signals to peripheral oscillators in order to maintain circadian rhythms in these tissues. There could be a time delay in the receipt of these SCN signals, or the signals may be sent at different times of the day for different tissues depending on their function. For example, certain metabolic pathways have to be activated in muscles at a particular time of the day while simultaneously reducing the activity of the GI tract(Reference Kreier, Kalsbeek and Ruiter41). Thus, the opposing autonomic tone redirects blood away from the abdomen towards tissues involved in movement. The mechanisms by which the SCN accomplishes this task are not well understood but may involve humoral mediators such as prokineticin-2(Reference Li, Hu and Boehmer42, Reference Prosser, Bradley and Chesham43), arginine vasopressin(Reference Kalsbeek, Fliers and Hofman44, Reference Kalsbeek, Buijs and van Heerikhuize45), cardiolipin-like cytokine(Reference Kraves and Weitz46), vasoactive intestinal polypeptide(Reference Kalsbeek and Buijs47), orexin(Reference Yi, Serlie and Ackermans48), pituitary adenylate cyclase-activating peptide(Reference Yi, Sun and Ackermans49) and transforming growth factor-α(Reference Li, Sankrithi and Davis50), or the release of the hormone melatonin by the pineal gland during darkness(Reference Moore51, Reference Engel, Lorenzkowski and Langer52). The SCN can also communicate time-of-day signals to peripheral tissues via neural outputs, such as the rhythmic change in the parasympathetic/sympathetic balance(Reference Kalsbeek, Foppen and Schalij53, Reference Buijs, La Fleur and Wortel54). The sympathetic projection, in particular, is critical in maintaining the physiological rhythms in peripheral tissues, such as glucose homeostasis by the liver(Reference Cailotto, La Fleur and van55, Reference Kalsbeek, Ruiter and La Fleur56). Moreover, the selectivity in communication between the SCN and peripheral tissues is such that parasympathetic and sympathetic branches of the autonomous nervous system are able to innervate different compartments within the same tissue. For example, the subcutaneous and intra-abdominal fat pads are innervated by separate parasympathetic and sympathetic motor neurons(Reference Kreier, Fliers and Voshol57). The sympathetic input to adipocytes has been reported to be essential for the regulation of daily rhythms in leptin release from the fat depot(Reference Kalsbeek, Fliers and Romijn58). Thus, altered autonomic outflow from the SCN can result in an imbalanced rhythm between different fat compartments, and this may bring about increased fat accumulation and obesity(Reference Kobayashi, Oishi and Hanai59).

In addition to daylight, other zeitgebers are able to entrain the central and/or peripheral clock. These include body temperature, mealtimes, restricted feeding and scheduled physical exercise(Reference Schibler, Ripperger and Brown60Reference Buxton, Lee and L'Hermite-Baleriaux62). These zeitgebers are particularly important for the circadian clock system in peripheral tissues which cannot perceive daylight cues. In contrast, the central clock in the SCN is largely light responsive and can be entrained by the light–dark cycle(Reference Stokkan, Yamazaki and Tei63, Reference van Someren and Riemersma-van der Lek64). Moreover, the intercellular connections of the SCN clocks enable them to maintain coherence in generating rhythms indefinitely in vivo and for several weeks in brain explants(Reference Liu, Welsh and Ko65). In contrast, cells in the periphery are less communicative and rapidly desynchronise in animals with SCN lesions(Reference Guo, Brewer and Lehman66) or in tissue culture(Reference Yoo, Yamazaki and Lowrey40, Reference Kornmann, Schaad and Bujard67). Therefore, the rhythms generated by oscillators in peripheral tissues must be entrained by the central SCN clock so that they can be in synchrony with each other. For peripheral tissues involved in nutritional and metabolic processes, such as the stomach, intestine, liver and pancreas, feeding schedules and restricted feeding become powerful zeitgebers(Reference Schibler, Ripperger and Brown60, Reference Hirota and Fukada68). Importantly, alterations in these peripheral zeitgebers could uncouple the phases of the peripheral and central clocks. Under normal conditions, the SCN clock synchronises the oscillators in the periphery in an indirect fashion. Hence, when nocturnal feeding animals such as rodents are restricted to meals during the day, the rhythms in food anticipatory activity, energy metabolism and gene expression in peripheral tissues will entrain to the day(Reference Davidson, Castanon-Cervantes and Stephan34, Reference Escobar, Cailotto and Angeles-Castellanos69, Reference Mistlberger70), while gene expression rhythms in the SCN remain entrained to the day–night cycle(Reference Dibner, Schibler and Albrecht11, Reference Stokkan, Yamazaki and Tei63). This may be viewed as an adaptive mechanism to changes in food availability while maintaining synchrony with the day–night cycle. The synchronisation of the peripheral clocks by feeding makes sense because circadian metabolism is a major clock output in many peripheral cells. However, long-term exposure to compounding effects of the different zeitgeber signals can result in poor metabolic health. Long-term shift work, frequent crossing of multiple time zones or irregular lifestyle with poor sleep, where changes in activity–sleep pattern are coupled with altered mealtimes, may also be considered risk factors in the development of various cardiometabolic and GI pathologies(Reference Knutsson and Boggild71Reference Scheer, Hilton and Mantzoros74).

Circadian clock system in extra-suprachiasmatic nuclei brain regions: how they regulate appetite and food intake

The canonical hypothalamic regions of the mammalian brain involved in food intake regulation include the lateral hypothalamus and the ventromedial nucleus, the former being associated with hunger and the latter linked to satiety(Reference Wynne, Stanley and McGowan75, Reference Funahashi, Takenoya and Guan76). In addition, neurons in other regions within the hypothalamus, including the dorsomedial, paraventricular and arcuate nuclei, secrete peptides that are involved in hunger and satiety. These neuropeptides can stimulate appetite, which include neuropeptide Y and Agouti-related protein, while others, including cocaine- and amphetamine-regulated transcript and pro-opiomelanocortin and its derivatives (e.g. α-melanocyte-stimulating hormone, melanocortin), diminish appetite(Reference Funahashi, Takenoya and Guan76, Reference Valassi, Scacchi and Cavagnini77). Gene and protein expression patterns of these neuropeptides exhibit a circadian rhythm in the rodent brain(Reference Lu, Shieh and Kabbaj78Reference Xu, Kalra and Farmerie80) and may therefore be required for the effect of circadian cues to affect appetite. In one study, it has been shown that increased food intake in mice at the onset of darkness is reduced in animals lacking neuropeptide Y(Reference Sindelar, Palmiter and Woods81). It further went on to show that mechanisms implicated with increased food intake brought about by food deprivation are distinct from those involved in response to feeding at the onset of the dark period of the light–dark cycle. Circadian rhythms in clock gene and protein expression have been shown in these regions of the rat brain by immunohistochemistry(Reference Feillet, Mendoza and Albrecht82, Reference Wyse and Coogan83), by in situ hybridisation(Reference Asai, Yoshinobu and Kaneko84) or by monitoring reporter constructs such as luciferase that is driven by clock gene promoters(Reference Abe, Herzog and Yamazaki85Reference Guilding, Hughes and Brown87). Currently, it is difficult to distinguish autonomous circadian rhythmicity in these extra-SCN brain regions from those imposed by inputs from the SCN. One could therefore assume that circadian rhythms of these peptides are dependent on the SCN. However, differential coupling of the extra-SCN clocks to their SCN counterparts due to multiple zeitgeber effects may result in changes in the phase, amplitude and phase-resetting kinetics in their oscillations, thus allowing plasticity of the circadian clock systems to integrate a wide range of temporal information.

Circadian rhythms of neuropeptides involved in appetite regulation may explain the persistent basic pattern of eating three meals per day in humans. This eating pattern has even been observed in individuals isolated from external time cues such as the day–night transition and day length(Reference Aschoff, von and Wildgruber88). A regular mealtime helps maintain a stable internal temporal order of the circadian clock system. Thus, abandonment of regular eating patterns due to the increasing demand imposed by contemporary 24 h societies may be disrupting nutritional and metabolic processes and can have profound effects on long-term health and well-being(Reference Fonken, Workman and Walton89Reference Morikawa, Nakagawa and Miura91).

The metabolic status of an individual is also transmitted in a circadian-dependent manner via humoral signals from peripheral tissues to the brain regions that control appetite(Reference Kalra, Bagnasco and Otukonyong92). The hormone leptin, which suppresses appetite and is produced primarily in adipocytes, is secreted in a circadian manner(Reference Lecoultre, Ravussin and Redman93, Reference Wong, Licinio and Yildiz94) and is therefore suggested to be under the control of the SCN clock via its sympathetic input to the adipocytes(Reference Kalsbeek, Fliers and Romijn58). In humans, night-time plasma leptin levels are high when appetite decreases, favouring fasting and nocturnal rest, and low during the day, when hunger increases. In obese individuals, however, daytime and night-time leptin levels are much higher compared with lean healthy subjects, indicating a state of leptin resistance(Reference Yildiz, Suchard and Wong95). Nevertheless, the circulating diurnal leptin rhythm is maintained. Leptin is also expressed in non-adipose tissues such as the stomach(Reference Cinti, Matteis and Pico96, Reference Bado, Levasseur and Attoub97). Gastric leptin levels oscillate in a circadian manner where leptin levels are high at night but low during the day(Reference Cinti, De and Ceresi98). This would suggest that gastric leptin is involved in regulating appetite by inducing satiety. One other hormone that reciprocates the action of leptin on appetite is ghrelin. Ghrelin is produced in the stomach and in other tissues including the pancreas and hypothalamus(Reference Kojima and Kangawa99, Reference Cowley, Smith and Diano100). It is involved in stimulating appetite via its action on neuropeptide Y in the lateral hypothalamus(Reference Chen, Trumbauer and Chen101, Reference Hagemann, Meier and Gallwitz102) and can also alter clock function in the SCN in vitro (Reference Yi, Challet and Pevet103, Reference Yannielli, Molyneux and Harrington104). Ghrelin oscillates with feeding(Reference Cummings, Purnell and Frayo105), making this peptide a putative candidate for food-related entraining signals. In addition, elevated levels of ghrelin were found during the early part of the night in sleeping subjects, decreasing in the morning before awakening(Reference Cummings, Purnell and Frayo105). Sleep deprivation can increase circulating ghrelin levels and this is accompanied by heightened hunger sensation(Reference Schmid, Hallschmid and Jauch-Chara106). Thus, ghrelin may be a signal involved in the cross-talk between the peripheral and central circadian clock system. However, circulating ghrelin levels are lower in obese individuals(Reference Tschop, Weyer and Tataranni107), whereas in anorectic patients, fasting ghrelin levels are significantly higher than in control subjects(Reference Otto, Cuntz and Fruehauf108). The temporal relationship between ghrelin and leptin indicates that, apart from the increase in serum ghrelin levels during the early part of the night, the diurnal rhythm of ghrelin is actually in-phase with that of circulating leptin levels. Hence, the night-time increase in circulating ghrelin levels may offset the appetite-suppressive effect produced by increased leptin. Interestingly, this temporal relationship is evident in both humans and rodents whose eating patterns are completely different(Reference Cummings, Purnell and Frayo105, Reference Sanchez, Oliver and Pico109).

In parallel to the circadian changes in neuropeptide levels and humoral signals from peripheral tissues, there also exists a circadian rhythm in macronutrient selection. In most mammals, the time of the day can influence the choice and quantity of macronutrient that is consumed. It has been shown in rats that at the beginning of their active phase at night when their glycogen reserves are low, their preference for carbohydrate increases with parallel increases in neuropeptide Y levels in the paraventricular nucleus of the hypothalamus(Reference Tempel and Leibowitz110, Reference Leibowitz111). By the end of their activity phase early in the morning, preference shifts to fat over protein and carbohydrates, which release energy more slowly over the resting phase(Reference Lax, Larue-Achagiotis and Martel112). Similarly in humans, a carbohydrate-rich diet is favoured during breakfast and high-fat diets are preferred during evening meals(Reference Westerterp-Plantenga, Ijedema and Wijckmans-Duijsens113). Carbohydrates are metabolised better during breakfast because the body is metabolically poised to respond to a glucose stimulus(Reference Dos Santos, Aragon and Padovani114). It is therefore sensible to ingest a sufficient quantity of energy that will enable the individual to become more alert and thus break the lethargy upon waking. On the other hand, circulating glucose levels are lower during sleep, when GI transit slows down, so it would be logical to think that an evening meal should not contain too much carbohydrate. Nevertheless, it remains to be elucidated whether the distribution of the macronutrients during the day is associated with obesity.

Circadian clock system in the gastrointestinal tract and its effect on the digestive cycle

Studies in rodents have shown that the GI tract contains functional clock genes(Reference Hoogerwerf, Hellmich and Cornelissen36, Reference Sladek, Rybova and Jindrakova115, Reference Polidarova, Sladek and Sotak116). The presence of these clock genes in the myenteric plexus, which acts as the local nervous system within the digestive system, and in the epithelial cells suggests that clock genes are involved in the generation of daily rhythms of GI function and activities, such as gastric emptying, colonic motility, gastric secretion and enzymatic activities, maintenance and repair of protective mucosal barriers, nutrient transport in the small intestine, and epithelial cell proliferation(Reference Bjarnason and Jordan117, Reference Scheving and Russell118). Rhythmic expression of these clocks can also vary between sections of the GI tract. In one such study, it has been reported that the rhythms of clock genes in the duodenum were phase-advanced to rhythms in the colon(Reference Polidarova, Sotak and Sladek119), and parallel the direction of the passage of food through the gut.

The production and secretion of various key metabolites in the GI tract(Reference Scheving and Russell118, Reference Hoogerwerf120) and gastric secretions(Reference Hoogerwerf120Reference Moore and Englert122) also display circadian rhythmicity. In diurnal species including humans, gastric secretions in the fasted state are at their maximum during the night and low in the morning(Reference Hoogerwerf120, Reference Moore and Englert122). This is coupled to slower gastric emptying and intestinal absorption rates after an evening meal compared with rates after morning meals(Reference Goo, Moore and Greenberg123). Nocturnal species such as the rat also exhibit high gastric secretion during the dark phase when gastric pepsin is low(Reference Moore, Larsen and Barattini124).

The circadian clock system in the intestine could also play an important role in nutrient absorption. Fats, carbohydrates and proteins are hydrolysed in the small intestine and the products of this hydrolysis are absorbed via intrinsic membrane transporter proteins. Interestingly, gene expression levels of these transporters exhibit circadian rhythmicity. In rodents, the Na-glucose transporter SGLT1, the GLUT GLUT2 and GLUT5(Reference Fatima, Iqbal and Houghton125Reference Pan, Terada and Okuda127), and the proton-coupled oligopeptide transporter 1(Reference Pan, Terada and Irie128, Reference Saito, Terada and Shimakura129) show peak expression at night. The circadian rhythms of these nutrient transporters are lost in Clock-mutant mice(Reference Pan and Hussain130) but is maintained in food-deprived animals(Reference Pan, Terada and Okuda131), suggesting that the circadian clock system in the intestinal lumen is more important in the regulation of these transporters than the presence of food. The significance of the circadian clock system in the small intestine may therefore lie in its ability to anticipate luminal food exposure which would allow the intestinal epithelium and its transporter system to be optimally prepared for the absorption of nutrients.

Indigestible food, on the other hand, that is unable to pass through the pylorus of the stomach to the duodenum (i.e. beginning of the small intestine) is emptied by a powerful muscular contraction propagated by the migrating myoelectric complex. In healthy individuals, the speed of migrating myoelectric complex propagation during the day is more than double compared with night-time values(Reference Kumar, Wingate and Ruckebusch132). Likewise, colonic motility is lower in the evening but increases during the day, particularly following awakening or following a meal(Reference Rao, Sadeghi and Beaty133). Thus, in humans, healthy individuals have bowel movements more often during the waking hours in the morning or subsequent to a meal but rarely during the night.

Since clock genes of the GI tract are expressed in a circadian manner, they are likely to be important regulators of GI tract activity. Therefore, disruption in circadian rhythms such as in shift work or travel across multiple time zones can upset the natural processing of food by the GI tract and could lead to abdominal bloating, poor nutrient absorption, diarrhoea or constipation(Reference Vener, Szabo and Moore134). Understanding the mechanisms underlying circadian variations in GI tract activity might therefore be useful in the diagnosis and prevention of these GI disorders.

Circadian clock system in the liver and pancreas: how they affect metabolism

The liver plays an important role in adjusting metabolic processes to the daily feeding cycles. This role is manifested by the vast number and variety of genes and proteins in the liver shown to be expressed in a circadian manner, which strongly suggests that the circadian clock system is vital in liver physiology(Reference Kornmann, Schaad and Bujard67, Reference Storch, Lipan and Leykin135, Reference Reddy, Karp and Maywood136). In addition to the clock genes themselves exhibiting circadian rhythms(Reference Peirson, Butler and Duffield32, Reference Yoo, Yamazaki and Lowrey40, Reference Turek and Allada137), rhythms were also observed in those genes involved in vital liver-specific processes, including rate-limiting steps in urea, sugar, alcohol and bile metabolism(Reference Reddy, Karp and Maywood136). Urea formation is central to the function of the liver, and the proteins that control several steps in the urea cycle vary across the circadian cycle. In rodents, the majority of these proteins peak during the dark phase of the light–dark cycle when they are actively feeding, and digestion would present amino acids to the hepatocytes(Reference Davidson, Castanon-Cervantes and Stephan34). Key enzymes involved in cholesterol metabolism show robust peak levels during the dark period of the light–dark cycle(Reference Davidson, Castanon-Cervantes and Stephan34). Enzymes involved in fructose metabolism as well as those involved in glycolysis and steps in the citric acid cycle also exhibited rhythmic oscillations, with expression levels increasing during the dark phase of the cycle(Reference Reddy, Karp and Maywood136, Reference Panda, Antoch and Miller138). Moreover, the transcription of genes encoding these metabolic enzymes is elevated during the early part of the night in anticipation of the start of night-time feeding in rodents(Reference Davidson, Castanon-Cervantes and Stephan34, Reference Akhtar, Reddy and Maywood139). Thus, there is a synchronous activation of a plethora of genes and their constitutive proteins critical to metabolism. Such temporal regulation optimises hepatic processing of night-time meals and metabolic efficiency, and implicates food-entrained circadian regulation for most of the genes in the rodent liver. The hepatic circadian clock system is therefore likely to be important for many aspects of liver physiology, such as clearance of drugs and toxins, which is impaired in mice lacking clock-regulated transcription factors(Reference Gachon, Olela and Schaad140).

In humans, it is difficult to directly assess the circadian clock system in the liver so proxy parameters are used, such as plasma glucose levels and insulin production. Humans show high glucose levels and insulin secretion rates shortly before awakening in anticipation of glucose demand during the active period(Reference Kalsbeek, Yi and La Fleur141, Reference Simon, Weibel and Brandenberger142). This would suggest that under normal feeding conditions, these rhythms are regulated by the circadian clock system in the SCN and not by the rhythms in food intake(Reference La Fleur, Kalsbeek and Wortel143, Reference La Fleur, Kalsbeek and Wortel144). Daily rhythms in glucose tolerance have also been reported, with a lower plasma glucose response to bolus glucose administration in the morning compared with responses in the evening(Reference Lee, Ader and Bray145, Reference Carroll and Nestel146). Interestingly, even though humans are active during the light phase of the light–dark cycle and rodents are active during the dark phase, both shows similar variations in glucose and insulin concentrations in the dark phase of the cycle(Reference Cuesta, Clesse and Pevet147).

In the pancreas, the role of the circadian clock system has only been recently elucidated. The pancreas regulates sugar and fat metabolism via controlled production of digestive enzymes and hormones in response to food availability and physiological demands. Circadian rhythms in pancreatic enzyme secretion are well documented in rodents, showing a night-time increase in amylase and the rate-limiting enzyme ornithine decarboxylase in polyamine biosynthesis(Reference Maouyo, Sarfati and Guan148, Reference Langlois and Morisset149). Rodent studies have also shown that clock genes are expressed in a circadian manner in the pancreas, particularly in the insulin-producing β-cells of the islets of Langerhans(Reference Sadacca, Lamia and deLemos38, Reference Muhlbauer, Wolgast and Finckh150). Normally after meals, the β-cells produce insulin to stimulate glucose uptake and storage by the muscle and fat cells, and also to stop glucose production and secretion by the liver. The importance of the circadian clock system is therefore reflected by a robust circadian pattern of insulin release in isolated pancreatic islet(Reference Peschke and Peschke151). Hence, loss of clock function in the pancreas can lead to metabolic disease pathologies. In studies using mice lacking one of the essential clock genes, Bmal1, in the pancreas, severe glucose intolerance and defective insulin production were observed, triggering the onset of a diabetes mellitus-like phenotype(Reference Marcheva, Ramsey and Buhr37, Reference Sadacca, Lamia and deLemos38). Moreover, the pancreatic islets in these mutant mice were found to be smaller and less efficient in producing insulin. In human subjects, circadian variation in the secretion of the pancreatic enzymes amylase and trypsin has been reported(Reference Keller, Groger and Cherian121, Reference Keller and Layer152). There is also a well-defined circadian rhythm of insulin secretion rates, where plasma insulin levels increase in the early morning, peaking by the afternoon and declining during the night(Reference Boden, Chen and Polansky153).

The effect of the food-entrainable zeitgeber on the circadian clock function

The preceding sections have highlighted the circumstances by which changes in the feeding schedule in nocturnal rodents can alter the rhythmic expression of circadian clock genes in the GI tract, liver and pancreas, without necessarily altering the expression pattern of the central clock in the SCN(Reference Hoogerwerf, Hellmich and Cornelissen36, Reference Stephan154). Hence, food is a very potent zeitgeber for peripheral clock systems. If rodents have access to food only during the light period when they are normally asleep, they will adjust to this feeding schedule within a few days and will display food anticipatory activity, including increased locomotor activity, body temperature, digestive enzyme activity and GI motility, a few hours before food becomes available(Reference Stephan154Reference Boulamery-Velly, Simon and Vidal156). Moreover, clock gene expression rhythms in these organs shift to realign with the new feeding schedule(Reference Schibler, Ripperger and Brown60, Reference Stokkan, Yamazaki and Tei63). These circadian activities are normally entrained by the central clock in the SCN. Thus, it would appear that clock gene expression in these organs, which are intimately involved in feeding, have become entrained to changes in the timing of feeding. Nonetheless, when the animals regain access to food during the dark period, the clock system in the SCN, whose rhythms remained unaffected by changes in the feeding schedule, regains the control of and re-entrains the peripheral clocks.

It remains unclear what signals associated with feeding cause the shifting of clock gene expression in peripheral tissues. Total parenteral nutrition, which bypasses the GI tract, during the light period in rats shifted the peak expression of hepatic clock genes(Reference Miki, Yano and Iwanaga157). This would suggest that factors directly associated with feeding, such as the taste of food, stomach distension, or direct physical contact of food with the GI lining, are not involved in entraining clock gene expression. In fact, nutrient availability at a cellular level has the greatest influence on molecular changes in the peripheral clock system. In addition, others have suggested that palatability as well as the nutritional value of the diet plays some role in entraining food anticipatory activity(Reference Mistlberger and Rusak158, Reference Hsu, Patton and Mistlberger159).

It remains a point of contention whether food anticipatory activity requires a food-entrainable oscillator since it is unlikely that the SCN clock is responsible for the changes in peripheral clock gene expression in response to timed feeding(Reference Storch and Weitz160). In SCN-lesioned rats, food anticipatory activity is still evident(Reference Stephan161) Therefore, the question remains, whether a second neuronal circadian system exists that can be entrained by the feeding schedule and has an influence over circadian rhythms in peripheral tissues. The exact location of this putative oscillator remains uncertain. Initially thought to be located in the GI tract, recent studies have suggested that at least important components of this food-entrainable oscillator are located in the dorsomedial hypothalamic nucleus(Reference Mieda, Williams and Richardson162, Reference Gooley, Schomer and Saper163). Ablation of this nucleus resulted in the abolition of food anticipatory activity and the pre-meal rise in body temperature(Reference Gooley, Schomer and Saper163). Nevertheless, one can argue that the central clock can still synchronise the clocks in peripheral tissues indirectly through its influence on the rest–activity cycles, which in turn drives humoral outputs resulting in feeding rhythms.

From an adaptive point of view, food anticipatory activity allows the organism to activate its arousal, appetite, digestive secretions and metabolism just before receiving food, allowing it to cope advantageously with predictable feeding availability. Hence when food is abundant, the light-entrainable oscillator in the SCN becomes responsible for driving circadian rhythms, but when food is scarce or is only available at certain times, the food-entrainable oscillator takes charge of a subset of rhythms, thus improving food access, but without encroaching on other rhythmic processes which continue to be governed by the light-entrainable SCN(Reference Stephan154, Reference Fuller, Lu and Saper164).

Poor nutrition can deregulate the clock system and increase the risk of metabolic disease

It is clear that the circadian clock system is profoundly influenced by nutrient intake. Therefore, it is unsurprising that excessive or imbalanced diets can have negative effects on the orchestration of core clock genes and their downstream transcriptional targets. A recent study in mice has shown that rhythmic expression of the clock gene Rev-erbα, which links circadian rhythms and metabolism in peripheral tissues, is disrupted in pancreatic β-cells in response to high-fat diet exposure(Reference Vieira, Marroqui and Batista165). In addition, the rhythmic pattern of insulin secretion was impaired, which suggests that Rev-erbα plays an important role in β-cell adaptation to nutritional stimuli. Thus, the plasticity of the clock system appears to become a maladaptive process when the organism is exposed to an obesogenic diet. In another study in mice, exposure to high-fat nutrition resulted in long-term abnormal clock and clock-controlled gene expression patterns in peripheral tissues such as the liver(Reference Hsieh, Yang and Tseng166). Similar observations have also been made in adipose tissue and the hypothalamus, whereby high-fat nutrition does not only induce molecular alterations in the clock system, but also changes behaviour rhythms(Reference Kohsaka, Laposky and Ramsey167). Collectively, these data imply that poor diets can cause an imbalance in the molecular components of both the peripheral and central clock systems. Since many of the clock-controlled genes have direct metabolic outputs, diet-induced perturbations in core clock genes can directly lead to altered metabolism, leading to an increased risk of metabolic disease. This notion is supported by studies in mice whereby inactivation of the key clock components Bmal1 and Clock resulted in metabolic pathologies such as obesity, fatty liver, hyperinsulinaemia, hyperglycaemia, hyperlipidaemia and hyperleptinaemia(Reference Marcheva, Ramsey and Buhr37, Reference Turek, Joshu and Kohsaka168, Reference Rudic, McNamara and Curtis169); co-existing pathologies which bear a striking resemblance to the human metabolic syndrome. The dramatic rise in the prevalence of the metabolic syndrome in recent times necessitates the need to understand its pathogenesis. Therefore, the circadian clock system is now an emerging research target and a putative candidate mechanism linking dietary influences to metabolic disease susceptibility.

Concluding statements

The circadian clock system is fundamental to a range of physiological processes as demonstrated by the temporal and pronounced activity of a plethora of systems involved in nutrition and metabolism. Disrupted circadian rhythms can lead to attenuated circadian feeding rhythms, hyperphagia, GI pathologies, metabolic disease and reduced life expectancy. As food components and feeding time have the ability to reset biological rhythms, it is of paramount importance to understand the relationship between food, feeding and the circadian clock system. In so doing, we may be able to use food or feeding times as a therapeutic intervention to reset or re-entrain the circadian clock system for better functionality of physiological systems, preventing obesity, promoting well-being and extending lifespan.

Acknowledgements

We acknowledge the financial support of the Biotechnology and Biological Sciences Research Council (grant no. BB/G01812X/1 to F. R. C.). Both authors declare that there are no conflicts of interest.

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Figure 0

Fig. 1 The core mechanism of the circadian clock in the suprachiasmatic nuclei and peripheral tissues. The cellular oscillator is composed of a positive limb (circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like protein 1 (BMAL1)) and a negative limb (cryptochrome (CRY) and period (PER)). CLOCK and BMAL1 dimerise in the cytoplasm and translocate to the nucleus. The CLOCK–BMAL1 heterodimer then binds to enhancer (E-box) sequences located in the promoter region of the Per and Cry genes, as well as other clock-controlled genes (CCG) activating their transcription. After translation, PER and CRY undergo nuclear translocation and inhibit CLOCK–BMAL1, resulting in decreased transcription of their own genes. Casein kinase 1 epsilon (CK1ɛ) periodically binds to and phosphorylates the PER proteins, which form heterodimers with each other and interact with CRY. The phosphorylation of the PER proteins prevents nuclear entry and also increases their ubiquitination, which leads to degradation. However, this can be overcome when the PER–CK1ɛ protein complex is bound to CRY. The autoregulatory transcription–translation loop comprising CLOCK–BMAL1 and PER–CRY constitutes the core clock and generates 24 h rhythms of gene expression. Retinoic acid receptor-related orphan receptor α (RORα) stimulates and reverse erythroblastosis virus α (REV-ERBα) inhibits Bmal1 transcription.

Figure 1

Fig. 2 The mammalian circadian clock system and its link to nutrition and metabolism. Photic signals received by retinal cells in the eyes are conveyed to the master clock in the suprachiasmatic nucleus (SCN) via the retinohypothalamic tract (RHT). The clock system in the SCN then conveys this zeitgeber to peripheral clock systems in the liver, pancreas and gastrointestinal (GI) tract via humoral and neuronal signals, which in turn regulate rhythms in nutritional and metabolic processes. Feeding rhythms, including food anticipatory activities, are also regulated by the master SCN clock. Nutritional zeitgebers such as malnutrition (over- or undernutrition) and restricted mealtimes can also entrain the clock systems and rhythmic processes in peripheral tissues, as well as feeding rhythms via a food-entrainable oscillator in non-SCN regions of the brain. DMH, dorsal medial nucleus of hypothalamus.