Circadian rhythms and appetite

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The control of food intake is a flexible system whereby internal and external environmental cues can alter the timing of feeding and appetite. The suprachiasmatic nucleus in the hypothalamus is the vital coordinator of these stimuli that ultimately generates fluctuations in neuronal and hormonal activities that are known as circadian rhythms. Circadian rhythms are driven by the daily variations in ambient light, which, by alterating gene expression, elicit a host of physiological responses including fluctuations in the hormones involved in appetite and food intake. Various factors such as temperature and social cues influence circadian rhythms; indeed, food intake itself can regulate these rhythms, but the neural mechanisms by which this occurs remains elusive. It has recently been proposed that there is a ‘food entrainable oscillator’ that exists independently of the SCN, and which controls food anticipation activity. The importance of circadian rhythms for ensuring good health has been highlighted by our modern day lifestyle, as jet-lag and shift work have shown that disruption of these delicate balances can lead to pathologies such as metabolic syndrome.

The generation of Circadian Rhythms: the clock genes

Clock mechanisms are formed by the transcription and translation of clock genes, which rely on feedback loops. In mammals, Clock and Bmal1 genes are part of the positive loop and Per genes, the negative loop. The clock genes regulate a self-sustaining rhythm in cells that even without light will maintain a roughly 24 hour rhythm. An extreme example is of cave fish which have lived in complete darkness for millions of years and their clock genes are still present in their DNA.

The rhythmic output of organs can be influenced by metabolic, endocrine and homeostatic events, as well as by the circadian clock. For example, the SCN can change the rhythm of expression of liver genes and enzymes without using clock genes, but through second messenger systems induced by the autonomic nervous system instead. Other genes can also affect circadian clock genes; for example the ROR-alpha gene is a positive regulator of Bmal1, which regulates lipogenesis and lipid storage.

Genes encoding core clock mechanism are circadian locomotor output cycles kaput (Clock), brain and muscle-Arnt-like 1(Bmal1), Period1 (Per1),Period2 (Per2), Period3 (Per3),Cryptochrome1(Cry1) and Cryptochrome2(Cry2). CLOCK (the protein product of Clock) is a transcription factor which dimerises with BMAL1 (the protein product of Bmal1) to activates transcription. CLOCK and BMAL1 are basic helix-loop-helix-PAS transcription factors which bind to E-box and E-box like promoter sequences activate transcription. The action of the CLOCK:BMAL1 heterodimer is inhibited by PER and CRY proteins. Products of Clock gene are important in regulating appetite. Mice whose Clock function was impaired had an increased food intake and rhythmic expression of Cart and Orexin hormones was eradicated . Experimental data reported by Bray et.al shows that CLOCK -/- mice exhibit obesity,altered feeding patterns,hyperphagia and hormonal abnormalities similar to those found in metabolic syndromes, such as hyperlipidemia, hyperleptinemia, hyperglycemia and hyperinsulinemia.

The SCN, circadian rhythms and feeding behaviour

A wide variety of organisms, from cyanobacteria to humans, all share common internal clock mechanisms that have been present for millions of years in evolutionary history. The circadian clock in mammals is responsible for setting specific temporal patterns within our bodily systems, including many physiological functions (body temperature, melatonin release, glucocorticoid secretion) and behavioural functions (alertness, working memory,) in order to keep us alive and running smoothly.

The "master" circadian clock of mammals is in the suprachiasmatic nucleus (SCN) of the hypothalamus. The main input to the SCN consists of signals encoding light; these are carried from the retina to the SCN by the retinohypothalamic tract. Vasoactive intestinal polypeptide, released from a subpopulation of neurones in the SCN, activates and synchronises other SCN neurons, the output of which coordinates behavioural rhythms. The main way in which the SCN regulates food intake is by directing the sleep/wake cycle.

The role of the SCN in feeding patterns has been determined using rodents, as their food intake is less influenced by cognition and social behaviour than that of humans. The sleep/wake cycle is driven by fluctuations in two main hormones: corticosterone (cortisol in humans) and melatonin. In rats, corticosterone secretion increases during the night when these nocturnal animals are active. This rise is followed by an increase in locomotor activity, in which rats forage for food and subsequently begin to feed. Melatonin is an important hormone that is released from the pineal gland during the night (the day in noturnal animals) which amongst its many actions induces sleep and suppresses appetite.

SCN regulation of the sleep/wake cycle

.Figure 2 (Adapted from figure 2c&d Saper et al. 2005). The SCN innervates multiple regions of the brain that regulate the sleep-wake cycle. a) The most intense output from the SCN is into the ventral sub-paraventricular zone (SPZ) which then projects into the dorsomedial hypothalamus (DMH) which in turn controls a wide range of circadian responses including corticosteroid secretion. The DMH innervates the medial parvicellular paraventricular nucleus (PVHm) and regulates the neurons containing CRH which in turn controls pituitary regulation of corticosteroid production. The SCN is also involved in regulating the release of melatonin from the pineal gland. The SCN projects into the dorsal parvicellular paraventricular nucleus, (PVHd) which subsequently project into sympathetic preganglionic neurons in the spinal cord which regulates melatonin output by the release of noradrenalin into the pineal gland. b) The DMH also has GABAergic projections into the ventrolateral preoptic nucleus VLPO (the sleep promoting region) and glutamatergic projections into the orexin producing neurons and the melanin-concentrating neurons in the lateral hypothalamus (LHA) which together regulate sleep and wakefulness and ultimately feeding. It is also apparent that hormones involved in appetite regulation such as ghrelin and leptin can influence these areas of the brain thus may have a role in resetting the circadian rhythms generated by the SCN.

Whilst the SCN is known to influence feeding patterns indirectly by regulating the awake/sleep cycles, there remains a possibility that the SCN may drive feeding patterns as the SCN appears to have reciprocal interactions with the orexigenic regions of the brain namely the lateral hypothalamus.

Adapted from Fig 3. Froy 2009.

PICTURE : It has been found that SCN fibres terminate in and around the arcuate nucleus (ARC) and the ventral part of the lateral hypothalamus (Yi et al. 2006). Activation of the arcuate nucleus releases NYP and AGRP (two potent orexigenic peptides) into the PVN which ultimately stimulates feeding and slows metabolism maximising energy intake .

Alternatively, it is possible that the SCN initiates feeding by conducting circadian rhythmic oscillations in the hormones involved in appetite. Indeed it has recently been established that a number of hormones involved in feeding behaviour and appetite, including leptin, and ghrelin show circadian oscillations . Leptin has been shown to exhibit circadian patterns in both gene expression and protein secretion in humans, with a peak during the sleep phase in humans (Kalra et al. 2003 in froy). Furthermore, rodent studies have shown that ablation of the SCN eliminates leptin circadian rhythmicity (Kalsbeek 2001 in Froy) and yet the role of the SCN in conducting this pattern is unclear. As leptin binds to receptors in the hypothalamus to suppress of appetite and an increase metabolism it seems plausible to suggest that the SCN can alter appetite indirectly via hormone regulation.

Whilst the role the SCN has in driving feeding behaviour remains elusive the latest research indicates that in addition to this central circadian clock there exists peripheral oscillators in other areas of the brain and other organs that produce rhythmic patterns in feeding time. Furthermore, it has been shown that rodents show food anticipatory behaviour indicating that these peripheral oscillators can be reset by feeding time itself thus have been named food entrainable oscillators. Moreover, it has been suggested that the SCN can signal to peripheral oscillators using signalling molecules such as TGF-alpha and prokinecticin 2 that prevent dampening of circadian rhythms in the tissues FROY. The recent study by Gilbert et al. 2009 have shown that transforming growth factor alpha is an important SCN peptide that regulates activity and feeding behaviour. Indeed intraperitoneal infusions of TGF-alpha was found to not only reduce locomotor activity but caused reduced food consumption and weight loss in syrian hamsters . Whilst the brain sites of action of TGF alpha in this experiment was found to be the brain it is also possible that they act outside the central nervous system.

Fiona E Graham 15:57, 25 October 2010 (UTC)

Peripheral Clocks and Food Entrainable Oscillators

Peripheral clocks

The SCN and peripheral clocks are not affected by meal timings, but restriction of food is the dominant synchroniser for peripheral clocks. When rats are restricted of food, metabolic and hormonal factors used by the SCN to drive peripheral oscillators are uncoupled, to shift to food time. Normally, the SCN and peripheral oscillators will work together as one unit, but a change in food availability can uncouple them in order for survival, when feeding is low and shifted from their normal place in the light-dark cycle..

© Image
SCN and Peripheral Oscillator Interaction.

The Food Entrained Oscillator

The FEO is a mysterious circadian clock, which is independent of the SCN. It ensures that when food is scarce, the body is still ready to digest and extract nutrients from the food that has been found, the FEO is responsible for anticipation of meal-time (FAA) .

Clock genes may contribute to the FAA but are not essential – Pendergast et al (2009) showed that animals without essential clock genes Bmal1 or per1 or2 were arrhythmic in constant darkness but still could express FAA. The FEO’s existence is putative, and its network is believed to be scattered over several brain regions. For example, the dorsomedial hypothalamic nucleus has been reported for FAA expression and the possible site of the FEO. The circadian mechanism for the FEO is unknown, but it does present clear circadian features.

Laura Sheldon 19:09, 24 October 2010 (UTC)Laura

Sleep deprivation, shift-work and appetite

PD Diagram
The relationship between sleep duration and changes in serum leptin and ghrelin levels. (a) Mean leptin levels against average nightly sleep duration. As the number of hours sleep increases, the levels of serum leptin also increase. Standard errors for half-hour increments of average nightly sleep. (b) Mean ghrelin levels against total number of hours sleep. As the total number of hours sleep decreases, the mean levels of ghrelin increase. Standard errors for half-hour increments of total sleep time. Adapted from Taheri et. al (2004)

In modern society, where shopping, eating, working and drinking are widely available 24hours a day,major health implications have been linked as a result. This availability of around the clock activities has defied our bodies internal clock of the vital hours of sleep it requires . Over the last few decades where technology and social activities has dramatically advanced, the number of hours of sleep young adults get has decreased within the range of 1-2hours . This is strongly correlated with the prevalence of obesity within the U.K which has shown to have trebled over the last 3 decades . Although the rise in this obesity epidemic has been shown to be multi-factorial, sleep deprivation is just another factor to add to the list needing to be addressed in this ever rising health problem.

Several epidemiologic studies have shown that sleep deprivation elevates the levels of the appetite stimulating hormone ghrelin and decreases circulating leptin levels [Fig. 5.1] . These changes could be the causes of increased food intake in these sleep- deprived adults where a rise in body weight is also observed [Fig. 5.2] . It is therefore important to fully understand the health implications that sleep-deprivation, associated with jetlag and night shift workers, has on the body in order to develop future therapeutic schemes against such related disorders as obesity.

The relationship between average nightly sleep and changes in body mass index (BMI). As the average nightly hours of sleep decreases below 7 hours, the mean BMI increases. Furthermore, more than an average of 8 hours sleep also causes a rise in mean BMI. Standard errors for 45-min intervals of average nightly sleep. Adapted from Taheri et. al (2004).

Conclusion

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