Circadian rhythms and appetite

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Introduction

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 neuronal and hormonal activities known as circadian rhythms.

Circadian rhythms are driven by the light and dark cycles of the earth which through alteration of gene expression elicit a host of physiological responses including fluctuations in the hormones involved in appetite and food intake.

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, such as general 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 found in the suprachiasmatic nucleus (SCN) of the hypothalamus. Circadian signals from the SCN are distributed by diffusible/humoral messages and by neuronal outputs . These signals influence clocks found in peripheral tissues (liver, kidney, thymus, muscle –Guillaumend et al 2005). Other brain regions express clock genes with self-sustained oscillations (retina, olfactory bulb and striatum), but these don’t have clocks.

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..

Rhythmic output of organs can be influenced by metabolic, endocrine and homeostatic events, as well as the circadian clock. For example, the SCN can change the rhythm of liver genes and enzymes without using clock genes, but through 2nd messenger systems induced by the ANS instead. Also other genes can have effect on circadian clock genes, for example ROR-alpha gene is a positive regulator of Bmal1 gene, which regulates lipogenesis and lipid storage (Lau et. Al 2004).

It has been well documented that food intake itself can regulate these rhythms and yet the neural mechanisms by which this occurs remains elusive. It has recently been proposed that there exists a ‘food entrainable oscillator’ that exists independently from the SCN which controls food anticipation activity.

Various factors such as have been known to influence circadian rhythms indeed our modern day lifestyle has highlighted new factors that influence these delicate balances including jet-lag and shift work.

SCN, the biological clock

Suprachiasmatic Nucleus

Suprachiasmatic nucleus of the anterior hypothalamus is the main regulator of circadian rhythms. SCN is made of neuronal and glial cells, with most of the neurons being GABAergic. Main input into SCN is light. Light is transmitted from retina via the retinohypothalamic tract to SCN. (Froy, 2010) Vasoactive intrinsic polypeptide in SCN activates and synchronises SCN neurons and coordinates behavioural rhythms. SCN signals to peripheral oscillators using the following actors: TGFα, prokinecticin 2 and cardiotrophin like cytokine and neuronal connections to prevent dampening of circadian rhythms in the tissues. (Froy, 2010) SCN efferent fibres terminate around the arcuate nucleus of ventromedial hypothalamus (VMH) and paraventricular nucleus PVN, areas involved in regulation of food intake and corticosteroid release. (Froy, 2010) SCN innervates sub-paraventricular zone (SPZ) and dorsomedial hypothalamus (DMH) which in-turn innervate PVN and lateral hypothalamus, areas which regulate corticosteroid release and wakefulness / feeding cycle. (Froy, 2010) DMH regulates sleep-wakefulness and feeding cycles among others and degeneration of DMH results in severe impairment of those cycles. (Froy, 2010) SCN selectively innervates preautonomic nervous system neurons found in dorsal and ventral borders of PVN.As pre-autonomic neurons in the hypothalamus are connected to sympathetic and parasympathetic system, this allows SCN to control energy homeostasis. (Froy, 2010) SCN receives information on hormones and metabolites, which are present in the bloodstream and cannot cross blood-brain barrier, via its dense reciprocal interactions with ventromedial arcuate nucleus (vmARC). vmARC receives the above information through its connection with circumventricular median eminence. Circumventricular median eminence is a structure within the brain which is free of blood-brain barrier and hormones can easily reach their receptors on neurons. Gastrin-releasing peptide interacts with SCN and results in light-like resetting of SCN. (Froy, 2010)

~~Image Figure 3. SCN afferents and efferents. The SCN can be activated by light, hormones and nutrients, neuronal connections (green arrows).The SCN neuronal connections to the ARC, MPOA, PVN and SPZ (blue arrows) ARC is affected by hormones and nutrients directly. SPZ innervates the DMH, with DMH innervating PVN, VLPO and LH which coordinate corticosteroid production, sleep, feeding respectively. PVN and DMH regulate adipose tissue, liver and other peripheral tissues through autonomic nervous system (red arrows).

Clock Genes

~~ 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). (Froy 2010). CLOCK transcription factor dimerises with BMAL1 and activates transcription. CLOCK and BMAL1 are basic helix-loop-helix-PAS transcription factors which upon binding to E-box and E-box like promoter sequences activate transcription. The action of 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(Froy 2010). 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.

SCN & Feeding Time

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 studies as unlike humans their food intake is less influenced by cognition and social behaviour. The sleep/wake cycle is driven by fluctuations in two main hormones: corticosterone (cortisol in humans) and melatonin. Corticosterone levels rise during the night when the nocturnal animals active (). Their rise is followed by an increase in activity in which they 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 ().

PICTURE OF SCN CONTROLLING CORTISONE AND MELATONIN RELEASE Figure Legend: Glucocorticoids: GABAergic projections from the SCN inhibit neuronal activity in the PVN during the day (Feillet 2010). In the night these inhibitory signals are suppressed and glutamatergic neurons stimulate CRH release from the PVN. CRH in the hypothalamic-portal system then triggers the release of ACTH from anterior pituitary into the blood stream that ultimately causes the release of glucocorticoids from the adrenal cortex. Melatonin: The SCN is connected to the pineal gland by a multisynaptic pathway which successively includes neurons of the paraventricular nucleus of the hypothalamus and a number of other brain regions. The release of noradrenaline into the pineal gland during the night stimulates the melatonin synthesis pathway. The study by Perreau et al. (2004) found that the rhythm of melatonin synthesis is formed by a combination of inhibitory and stimulatory signals from the SCN to the PVN and that the SCN-derived glutamate release within the PVN is the main stimulus for melatonin synthesis.

Whilst the SCN is known to influence feeding patterns indirectly by regulating the awake/sleep cycles, it remains unclear whether or not the SCN can directly drive appetite. As the SCN has reciprocal interactions with the orexigenic regions of the brain it is possible that the SCN can directly stimulate appetite.

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 . However, research into this possibility is yet to be carried out.

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, ghrelin, and orexins show circadian oscillations. (Reviwed by Froy 2010). GRAPHS 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 (Schwartz et al. 2000) it seems plausible to suggest that the SCN can alter appetite indirectly via hormone regulation.

Conclusion…

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.. 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] .

Figure 5.2. 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. This figure has been adapted from Taheri et. al (2004).

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