Modulation of circadian clocks by nutrients and food factors

Daily activity rhythms that are dominated by internal clocks are called circadian rhythms. A central clock is located in the suprachiasmatic nucleus of the hypothalamus, and peripheral clocks are located in most mammalian peripheral cells. The central clock is entrained by light/dark cycles, whereas peripheral clocks are entrained by feeding cycles. The effects of nutrients on the central and peripheral clocks have been investigated during the past decade and much interaction between them has come to light. For example, a high-fat diet prolongs the period of circadian behavior, a ketogenic diet advances the onset of locomotor activity rhythms, and a high-salt diet advances the phase of peripheral molecular clocks. Moreover, some food factors such as caffeine, nobiletin, and resveratrol, alter molecular and/or behavioral circadian rhythms. Here, we review nutrients and food factors that modulate mammalian circadian clocks from the cellular to the behavioral level.     

Circadian molecular clocks tick along ontogenesis

The circadian system controls the timing of behavioral and physiological functions in most organisms studied. The review addresses the question of when and how the molecular clockwork underlying circadian oscillations within the central circadian clock in the suprachiasmatic nuclei of the hypothalamus (SCN) and the peripheral circadian clocks develops during ontogenesis. The current model of the molecular clockwork is summarized. The central SCN clock is viewed as a complex structure composed of a web of mutually synchronized individual oscillators. The importance of development of both the intracellular molecular clockwork as well as intercellular coupling for development of the formal properties of the circadian SCN clock is also highlighted. Recently, data has accumulated to demonstrate that synchronized molecular oscillations in the central and peripheral clocks develop gradually during ontogenesis and development extends into postnatal period. Synchronized molecular oscillations develop earlier in the SCN than in the peripheral clocks. A hypothesis is suggested that the immature clocks might be first driven by external entraining cues, and therefore, serve as "slave" oscillators. During ontogenesis, the clocks may gradually develop a complete set of molecular interlocked oscillations, i.e., the molecular clockwork, and become self-sustained clocks.     

Peripheral circadian oscillators in mammals: time and food

Peripheral cells from mammalian tissues, while perfectly capable of circadian rhythm generation, are not light sensitive and thus have to be entrained by nonphotic cues. Feeding time is the dominant zeitgeber for peripheral mammalian clocks: Daytime feeding of nocturnal laboratory rodents completely inverts the phase of circadian gene expression in many tissues, including liver, heart, kidney, and pancreas, but it has no effect on the SCN pacemaker. It is thus plausible that in intact animals, the SCN synchronizes peripheral docks primarily through temporal feeding patterns that are imposed through behavioral rest-activity cycles. In addition, body temperature rhythms, which are themselves dependent on both feeding patterns and rest-activity cycles, can sustain circadian, clock gene activity in vivo and in vitro. The SCN may also influence the phase of rhythmic gene expression in peripheral tissues through direct chemical pathways. In fact, many chemical signals induce circadian gene expression in tissue culture cells. Some of these have been shown to elicit phase shifts when injected into intact animals and are thus candidates for physiologically relevant timing cues. While the response of the SCN to light is strictly gated to respond only during the night, peripheral oscillators can be chemically phase shifted throughout the day. For example, injection of dexamethasone, a glucocorticoid receptor agonist, resets the phase of circadian liver gene expression during the entire 24-h day. Given the bewildering array of agents capable of influencing peripheral clocks, the identification of physiologically relevant agents used by the SCN to synchronize peripheral clocks will clearly be an arduous undertaking. Nevertheless, we feel that experimental systems by which this enticing problem can be tackled are now at hand.     

Signalling entrains the peripheral circadian clock

In mammals, 24-h rhythms of behaviour and physiology are regulated by the circadian clock. The circadian clock is controlled by a central clock in the brain's suprachiasmatic nucleus (SCN) that synchronizes peripheral clocks in peripheral tissues. Clock genes in the SCN are primarily entrained by light. Increasing evidence has shown that peripheral clocks are also regulated by light and hormones independent of the SCN. How the peripheral clocks deal with internal signals is dependent on the relevance of a specific cue to a specific tissue. In different tissues, most genes that are under circadian control are not overlapping, revealing the tissue-specific control of peripheral clocks. We will discuss how different signals control the peripheral clocks in different peripheral tissues, such as the liver, gastrointestinal tract, and pancreas, and discuss the organ-to-organ communication between the peripheral clocks at the molecular level.     

Clock genes in cell clocks: roles, actions, and mysteries

Cellular events must be organized in the time dimension as well as in the space dimension for many proteins to perform their cellular functions effectively. The intracellular molecular oscillating loops that compose the cell's circadian clock coordinate the timing of the expression of a variety of genes with basic or specific cellular functions. In mammals, the temporal pattern of clock gene expression generated in each SCN neuron is coupled to those of other cells and, amplified, spreads its signals through the brain and then, via feeding behavior, glucocorticoids, and sympathetic nerves, to peripheral organs. These peripheral organs have their own circadian clocks. In some tissues, such as liver, there is also a clock-regulating cell cycle, which interacts strongly with the components and temporal organization of the circadian clock. Some tissues, however, such as testis, express clock genes whose function, if any, remains unclear. Furthermore, circadian clock function may be suspended in differentiating tissue. Thus, the prominence of circadian organization may not apply equally to all tissues under all conditions.     

Does the circadian system regulate lactation?

Environmental variables such as photoperiod, heat, stress, nutrition and other external factors have profound effects on quality and quantity of a dairy cow's milk. The way in which the environment interacts with genotype to impact milk production is unknown; however, evidence from our laboratory suggests that circadian clocks play a role. Daily and seasonal endocrine rhythms are coordinated in mammals by the master circadian clock in the hypothalamus. Peripheral clocks are distributed in every organ and coordinated by signals from the master clock. We and others have shown that there is a circadian clock in the mammary gland. Approximately 7% of the genes expressed during lactation had circadian patterns including core clock and metabolic genes. Amplitude changes occurred in the core mammary clock genes during the transition from pregnancy to lactation and were coordinated with changes in molecular clocks among multiple tissues. In vitro studies using a bovine mammary cell line showed that external stimulation synchronized mammary clocks, and expression of the core clock gene, BMAL1, was induced by lactogens. Female clock/clock mutant mice, which have disrupted circadian rhythms, have impaired mammary development and their offspring failed to thrive suggesting that the dam's milk production was not adequate enough to nourish their young. We envision that, in mammals, during the transition from pregnancy to lactation the master clock is modified by environmental and physiological cues that it receives, including photoperiod length. In turn, the master clock coordinates changes in endocrine milieu that signals peripheral tissues. In dairy cows, it is clear that changes in photoperiod during the dry period and/or during lactation influences milk production. We believe that the photoperiod effect on milk production is mediated, in part by the 'setting' of the master clock with light, which modifies peripheral circadian clocks including the mammary core clock and subsequently impacts milk yield and may impact milk composition.     

The comparison between circadian oscillators in mouse liver and pituitary gland reveals different integration of feeding and light schedules

The mammalian circadian system is composed of multiple peripheral clocks that are synchronized by a central pacemaker in the suprachiasmatic nuclei of the hypothalamus. This system keeps track of the external world rhythms through entrainment by various time cues, such as the light-dark cycle and the feeding schedule. Alterations of photoperiod and meal time modulate the phase coupling between central and peripheral oscillators. In this study, we used real-time quantitative PCR to assess circadian clock gene expression in the liver and pituitary gland from mice raised under various photoperiods, or under a temporal restricted feeding protocol. Our results revealed unexpected differences between both organs. Whereas the liver oscillator always tracked meal time, the pituitary circadian clockwork showed an intermediate response, in between entrainment by the light regimen and the feeding-fasting rhythm. The same composite response was also observed in the pituitary gland from adrenalectomized mice under daytime restricted feeding, suggesting that circulating glucocorticoids do not inhibit full entrainment of the pituitary clockwork by meal time. Altogether our results reveal further aspects in the complexity of phase entrainment in the circadian system, and suggest that the pituitary may host oscillators able to integrate multiple time cues.     

Exploring the role of circadian clock gene and association with cancer pathophysiology

ABSTRACT

Most of the processes that occur in the mind and body follow natural rhythms. Those with a cycle length of about one day are called circadian rhythms. These rhythms are driven by a system of self-sustained clocks and are entrained by environmental cues such as light-dark cycles as well as food intake. In mammals, the circadian clock system is hierarchically organized such that the master clock in the suprachiasmatic nuclei of the hypothalamus integrates environmental information and synchronizes the phase of oscillators in peripheral tissues.

The circadian system is responsible for regulating a variety of physiological and behavioral processes, including feeding behavior and energy metabolism. Studies revealed that the circadian clock system consists primarily of a set of clock genes. Several genes control the biological clock, including BMAL1, CLOCK (positive regulators), CRY1, CRY2, PER1, PER2, and PER3 (negative regulators) as indicators of the peripheral clock.

Circadian has increasingly become an important area of medical research, with hundreds of studies pointing to the body’s internal clocks as a factor in both health and disease. Thousands of biochemical processes from sleep and wakefulness to DNA repair are scheduled and dictated by these internal clocks. Cancer is an example of health problems where chronotherapy can be used to improve outcomes and deliver a higher quality of care to patients.

In this article, we will discuss knowledge about molecular mechanisms of the circadian clock and the role of clocks in physiology and pathophysiology of concerns.