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{{Image|Arc.JPG|right|600px|'''The SCN and orexigenic regions of the brain.''' SCN fibres terminate in and around the arcuate nucleus (ARC) and the ventral part of the lateral hypothalamus <ref name=Yi06>Yi CX (2006)Ventromedial arcuate nucleus communicates peripheral metabolic information to the suprachiasmatic nucleus. ''Endocrinology'' 147:283–94</ref>.  Activation of the arcuate nucleus releases NYP and AgRP (two potent orexigenic peptides) into the PVN which ultimately stimulate feeding and slow metabolism <ref name=Schwartz00>Schwartz MW (2007)Central nervous system control of food intake ''Nature'' 404:661-671 </ref>. Adapted from Froy  2010 <ref name=Froy10/>}}


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The [[suprachiasmatic nucleus]] in the [[hypothalamus]] is the vital coordinator of the 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]]. 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 is independent of the SCN, and which controls food anticipation activity.


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==The clock genes==
Clock mechanisms in biological cells arise from cycles of [[transcription]] and [[translation]] of [[clock genes]]. The clock genes regulate a rhythm in cells that, even without light, will maintain a roughly 24 hour rhythm. An extreme example is of cave fish which have evolved in complete darkness for millions of years and their clock genes are still present in their DNA.<ref name=Mendoza09>Mendoza ''et al.''(2009) Brain clocks: From the suprachiasmatic nuclei to a cerebral network. ''The Neuroscientist'' 15:5</ref>


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Genes which encode important proteins of the core clock mechanism include ''Clock'' (circadian locomotor output cycles kaput); ''Bmal1'' (brain and muscle-Arnt-like 1); the ''Period'' genes ''Per1'', ''Per2'' and ''Per3''); and the ''Cryptochrome'' genes ''Cry1''  and ''Cry2''. CLOCK (the protein product of ''Clock'') is a [[transcription factor]] which dimerises with BMAL1 (the protein product of ''Bmal1''). CLOCK and BMAL1  form a complex which binds to E-box, a DNA sequence in the promoter region of the gene, and to other similar promoter sequences. The binding of the CLOCK:BMAL1 complex to the E-box in the promoter region of ""Per"" and ""Cry"" activates their transcription. In turn, the PER and CRY proteins can inhibit the CLOCK:BMAL1 complex, resulting in the decreased transcription of their own genes.<ref name=Froy10>Froy ''et al.''(2010) Metabolism and circadian rhythms—implications for obesity ''Endocr Rev'' 31:1-24</ref>


Construct your article in sections and subsections, with headings and subheadings like this:
Mice with impaired ''Clock'' function are obese, displaying altered feeding patterns, hyperphagia and abnormalities similar to those found in metabolic syndromes, such as hyperlipidemia (abnormally elevated levels of lipoproteins in the blood), hyperglycemia (high concentrations of glucose in blood) and hyperinsulinemia (excess of circulating insulin).<ref name=Froy10/>


==Introduction==
==The SCN, circadian rhythms and feeding behaviour==
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]]''.
{{Image|SCN.JPG|left|600px|'''SCN regulation of the sleep/wake cycle''';
The SCN innervates regions of the brain that regulate the sleep-wake cycle. a) The ventral sub-paraventricular zone (SPZ) projects to the [[dorsomedial hypothalamus]] (DMH) which controls many circadian responses including [[corticosteroid]] secretion. The DMH innervates the medial parvicellular [[paraventricular nucleus]] (PVHm) and regulates the neurons which control corticosteroid production.  The SCN also projects to the dorsal parvicellular paraventricular nucleus, (PVHd) which  projects to sympathetic preganglionic neurons which regulate [[melatonin]] output from the [[pineal gland]]. b) The DMH also has projections to the ventrolateral preoptic nucleus VLPO (the sleep promoting region) and to the [[orexin]] neurons and  [[melanin-concentrating hormone]] (MCH) neurons in the [[lateral hypothalamus]] (LHA) which together regulate sleep and wakefulness. 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. (Adapted from Saper ''et al.'' (2005)<ref>Saper A ''et al.'' (2005) The hypothalamic integrator for circadian rhythms ''Trends Neurosci'' 28:152-7</ref>)}}


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.  
The circadian clock in mammals sets specific temporal patterns within our bodily systems, including many physiological functions (body temperature, melatonin release, glucocorticoid secretion) and behavioural functions. The "master" circadian clock of mammals is in the [[suprachiasmatic nucleus]] (SCN) of the hypothalamus. This receives signals encoding light, which are carried from the retina to the SCN by the retinohypothalamic tract. [[Vasoactive intestinal polypeptide]], [[vasopressin]], [[somatostatin]] and other peptides, released from subpopulations of neurones in the SCN, activate and synchronise other SCN neurons, the output of which coordinates behavioural rhythms, including by directing the sleep/wake cycle. 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 they 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 and, amongst its many actions, it affects sleep and appetite. However, these hormones have different roles in different species. For example, melatonin is released during the night in both humans and rodents, and yet latter are nocturnal and therefore most active at night. This indicates that melatonin has opposite effects in rodents and humans in that it appears to drive the awake period in rats, but induces sleep  in humans. Thus whilst the SCN may regulate the sleep-wake cycle, this regulation is species-specific. Nevertheless, it is possible that the SCN may drive feeding patterns directly as the SCN has reciprocal interactions with orexigenic regions of the brain such as the lateral hypothalamus.  


Alternatively, the SCN may initiate feeding by conducting circadian rhythmic oscillations in the hormones involved in appetite. Indeed, a number of hormones involved in feeding behaviour and appetite, including leptin and ghrelin, show circadian oscillations. <ref name=Yildiz04>Yildiz BO (2004) Alteration in the dynamics of circulating [[ghrelin]], [[adiponectin]] and [[leptin]] in human obesity ''Proc Natl Acad Sci USA'' 101:10434-9</ref>. Leptin exhibits circadian patterns in both gene expression and protein secretion in humans, with a peak during sleep <ref name=Kalra03>Kalra SP(2003) Rhythmic, reciprocal ghrelin and leptin signaling: new insight in the development of obesity ''Regul Pept'' 111:1–11</ref>. In rodents, ablation of the SCN eliminates leptin circadian rhythmicity <ref name=Kalsbeek01>Kalsbeek A (2001) The suprachiasmatic nucleus generates the diurnal changes in plasma leptin levels ''Endocrinology'' 142:2677–85</ref> and yet the role of the SCN in conducting this pattern is unclear.


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.
Whilst the role the SCN has in driving feeding behaviour remains elusive, oscillators in other areas of the brain and other organs may also produce rhythmic patterns in feeding. Rodents show ''food anticipatory behaviour'' indicating that these peripheral oscillators can be reset by feeding time itself, thus have been named 'food entrainable oscillators'. It has been suggested that the SCN signals to these other oscillators using signalling molecules such as [[transforming growth factor alpha]] (TGF-alpha) and prokinecticin 2 that prevent dampening of circadian rhythms in the tissues <ref name=Froy10/>.  <ref name=Gilbert09>Gilbert J (2009) Behavioral effects of systemic transforming growth factor-alpha in Syrian hamsters ''Behav Brain Res'' 198:440-8</ref>
 
 
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 <ref>Kalsbeek ''et al.''(2007)  Minireview: circadian control of metabolism by the suprachiasmatic nuclei ''Endocrinology'' 148:5635-9</ref>. 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.<ref>Mendoza J, Challet E (2009) Brain clocks: From the suprachiasmatic nuclei to a cerebral network ''The Neuroscientist'' 15: 5 </ref>.
 
 
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 (Schwartz 2000). 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…
 
[[User:Fiona E Graham|Fiona E Graham]] 15:57, 25 October 2010 (UTC)


==Peripheral Clocks and Food Entrainable Oscillators==
==Peripheral Clocks and Food Entrainable Oscillators==
{{Image|Circ rhythm.JPG|right|700px|SCN and Peripheral Oscillator Interaction.}}
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 work together, but a change in food availability can uncouple them when environmental circumstances demand that feeding patterns are shifted from their normal place in the light-dark cycle.<ref>Escobar C ''et al.'' (2009)  Peripheral oscillators are important for food anticipatory activity (FAA) ''Eur J Neurosci'' 30:1665–75</ref>.


Peripheral clocks
The 'Food Entrained Oscillator' is a mysterious circadian clock, which is independent of the SCN. It ensures the body is ready to digest and extract nutrients from the food in anticipation of meal-time <ref name=Mendoza09/>. Clock genes may contribute to the Food Entrained Oscillator, but are not essential – animals without essential clock genes ''Bmal1'' or ''per1'' or ''per2'' were arrhythmic in constant darkness but still could express food anticipation. <ref>Pendergast ''et al''' (2009)</ref>
 
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.<ref>Escobar C ''et al.'' (2009)  Peripheral oscillators are important for food anticipatory activity (FAA)</ref><ref> Mendoza J. & Challet E. (2009)</ref>
 
 
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.
 
[[User:Laura Sheldon|Laura Sheldon]] 19:09, 24 October 2010 (UTC)Laura


==Sleep deprivation, shift-work and appetite==
==Sleep deprivation, shift-work and appetite==
In modern society, shopping, eating, working and drinking are widely available 24 hours a day. Over the last few decades, the number of hours of sleep young adults get has decreased by 1-2 hours. This is correlated with the prevalence of obesity within the U.K which has trebled over the last three decades. Although the rise in this obesity epidemic is multi-factorial, sleep deprivation may be another factor to add to the list needing to be addressed in this ever rising health problem. <ref>Gimble JM ''et al.'' (2009) Circadian biology and sleep: missing links in obesity and metabolism? ''Obesity Rev'' 10(suppl 2):1-5</ref> <ref>Rennie KL, Jebb SA (2005) Prevalence of obesity in Great Britain ''Obesity Rev'' 6:11-2</ref> <ref name=Spiegel04>Spiegel ''et al.''(2004) Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite ''Ann Internal Med'' 141:846-50</ref>. 


In modern society, where shopping, eating, working and drinking are widely available 24hours a day,{{Image|Fig 1.PNG|right|350px|'''Figure 5.1.  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 increases.  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 increases.  Standard errors for half-hour increments of total sleep time.  This figure has been adapted from Taheri ''et. al'' (2004).}} 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 <ref>Gimble JM ''et al.'' (2009) Circadian biology and sleep: missing links in obesity and metabolism? ''Obesity Rev'' 10(suppl 2):1-5.</ref>.  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 <ref name=Spiegel04>Spiegel ''et. al''(2004)Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite ''Ann Internal Med'' 141:846-50</ref>.  This is strongly correlated with the prevalence of obesity within the U.K which has shown to have trebled over the last 3 decades <ref>Rennie KL, Jebb SA (2005) Prevalence of obesity in Great Britain ''Obesity Rev'' 6:11-2</ref>.  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. 
Sleep deprivation elevates the circulating levels of the appetite stimulating hormone [[ghrelin]] and decreases those of [[leptin]]<ref name=Taheri04> Taheri ''et al.'' (2004) Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index ''PLoS Medicine'' 1:e62</ref><ref name=Spiegel04/>. These changes could be the causes of increased food intake in those sleep-deprived adults where a rise in body weight is also observed <ref name=Taheri04/>. It is therefore important to understand the health implications that sleep-deprivation, associated with jetlag and shift working, has on the body in order to develop therapeutic schemes against such related disorders as obesity.
 
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] <ref name=Taheri04> Taheri ''et al.'' (2004) Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index. ''PLoS Medicine'' 1(3):e62</ref><ref name=Spiegel04/>. 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] <ref name=Taheri04/>.
 
{{Image|Fig2.PNG|centre|350px|'''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).}}


==Conclusion==
==Conclusion==
etc.
Over the last decade, significant progress has been made in our understanding of the inter-relationship between circadian biology, sleep and metabolism in the context of obesity.  The SCN, which is a vital coordinator of circadian rhythms, may have a role in driving feeding patterns, along with other peripheral oscillators in the brain and organs that produce rhythmic patterns in feeding time. In the modern world, sleep deprivation is a growing issue of concern and the health implications need to be acknowledged. An adequate number of hours sleep each night is vital for a healthy life. Disruptions of the circadian variations in such appetite-regulating hormones as leptin and ghrelin may contribute to the development of obesity in sleep-deprived patients.  Gaps still remain in our knowledge of the underlying biological rhythms and its association with obesity. So far, therapeutic strategies have failed to curb the rising incidence of obesity, but if, through a greater understanding of these complex systems we can  control appetite, the benefits will be a healthier population and less strain on the health services.
 
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The SCN and orexigenic regions of the brain. SCN fibres terminate in and around the arcuate nucleus (ARC) and the ventral part of the lateral hypothalamus [1]. Activation of the arcuate nucleus releases NYP and AgRP (two potent orexigenic peptides) into the PVN which ultimately stimulate feeding and slow metabolism [2]. Adapted from Froy 2010 [3]

The suprachiasmatic nucleus in the hypothalamus is the vital coordinator of the 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. 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 is independent of the SCN, and which controls food anticipation activity.

The clock genes

Clock mechanisms in biological cells arise from cycles of transcription and translation of clock genes. The clock genes regulate a rhythm in cells that, even without light, will maintain a roughly 24 hour rhythm. An extreme example is of cave fish which have evolved in complete darkness for millions of years and their clock genes are still present in their DNA.[4]

Genes which encode important proteins of the core clock mechanism include Clock (circadian locomotor output cycles kaput); Bmal1 (brain and muscle-Arnt-like 1); the Period genes Per1, Per2 and Per3); and the Cryptochrome genes Cry1 and Cry2. CLOCK (the protein product of Clock) is a transcription factor which dimerises with BMAL1 (the protein product of Bmal1). CLOCK and BMAL1 form a complex which binds to E-box, a DNA sequence in the promoter region of the gene, and to other similar promoter sequences. The binding of the CLOCK:BMAL1 complex to the E-box in the promoter region of ""Per"" and ""Cry"" activates their transcription. In turn, the PER and CRY proteins can inhibit the CLOCK:BMAL1 complex, resulting in the decreased transcription of their own genes.[3]

Mice with impaired Clock function are obese, displaying altered feeding patterns, hyperphagia and abnormalities similar to those found in metabolic syndromes, such as hyperlipidemia (abnormally elevated levels of lipoproteins in the blood), hyperglycemia (high concentrations of glucose in blood) and hyperinsulinemia (excess of circulating insulin).[3]

The SCN, circadian rhythms and feeding behaviour

SCN regulation of the sleep/wake cycle; The SCN innervates regions of the brain that regulate the sleep-wake cycle. a) The ventral sub-paraventricular zone (SPZ) projects to the dorsomedial hypothalamus (DMH) which controls many circadian responses including corticosteroid secretion. The DMH innervates the medial parvicellular paraventricular nucleus (PVHm) and regulates the neurons which control corticosteroid production. The SCN also projects to the dorsal parvicellular paraventricular nucleus, (PVHd) which projects to sympathetic preganglionic neurons which regulate melatonin output from the pineal gland. b) The DMH also has projections to the ventrolateral preoptic nucleus VLPO (the sleep promoting region) and to the orexin neurons and melanin-concentrating hormone (MCH) neurons in the lateral hypothalamus (LHA) which together regulate sleep and wakefulness. 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. (Adapted from Saper et al. (2005)[5])

The circadian clock in mammals sets specific temporal patterns within our bodily systems, including many physiological functions (body temperature, melatonin release, glucocorticoid secretion) and behavioural functions. The "master" circadian clock of mammals is in the suprachiasmatic nucleus (SCN) of the hypothalamus. This receives signals encoding light, which are carried from the retina to the SCN by the retinohypothalamic tract. Vasoactive intestinal polypeptide, vasopressin, somatostatin and other peptides, released from subpopulations of neurones in the SCN, activate and synchronise other SCN neurons, the output of which coordinates behavioural rhythms, including by directing the sleep/wake cycle. 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 they 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 and, amongst its many actions, it affects sleep and appetite. However, these hormones have different roles in different species. For example, melatonin is released during the night in both humans and rodents, and yet latter are nocturnal and therefore most active at night. This indicates that melatonin has opposite effects in rodents and humans in that it appears to drive the awake period in rats, but induces sleep in humans. Thus whilst the SCN may regulate the sleep-wake cycle, this regulation is species-specific. Nevertheless, it is possible that the SCN may drive feeding patterns directly as the SCN has reciprocal interactions with orexigenic regions of the brain such as the lateral hypothalamus.

Alternatively, the SCN may initiate feeding by conducting circadian rhythmic oscillations in the hormones involved in appetite. Indeed, a number of hormones involved in feeding behaviour and appetite, including leptin and ghrelin, show circadian oscillations. [6]. Leptin exhibits circadian patterns in both gene expression and protein secretion in humans, with a peak during sleep [7]. In rodents, ablation of the SCN eliminates leptin circadian rhythmicity [8] and yet the role of the SCN in conducting this pattern is unclear.

Whilst the role the SCN has in driving feeding behaviour remains elusive, oscillators in other areas of the brain and other organs may also produce rhythmic patterns in feeding. Rodents show food anticipatory behaviour indicating that these peripheral oscillators can be reset by feeding time itself, thus have been named 'food entrainable oscillators'. It has been suggested that the SCN signals to these other oscillators using signalling molecules such as transforming growth factor alpha (TGF-alpha) and prokinecticin 2 that prevent dampening of circadian rhythms in the tissues [3]. [9]

Peripheral Clocks and Food Entrainable Oscillators

© Image
SCN and Peripheral Oscillator Interaction.

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 work together, but a change in food availability can uncouple them when environmental circumstances demand that feeding patterns are shifted from their normal place in the light-dark cycle.[10].

The 'Food Entrained Oscillator' is a mysterious circadian clock, which is independent of the SCN. It ensures the body is ready to digest and extract nutrients from the food in anticipation of meal-time [4]. Clock genes may contribute to the Food Entrained Oscillator, but are not essential – animals without essential clock genes Bmal1 or per1 or per2 were arrhythmic in constant darkness but still could express food anticipation. [11]

Sleep deprivation, shift-work and appetite

In modern society, shopping, eating, working and drinking are widely available 24 hours a day. Over the last few decades, the number of hours of sleep young adults get has decreased by 1-2 hours. This is correlated with the prevalence of obesity within the U.K which has trebled over the last three decades. Although the rise in this obesity epidemic is multi-factorial, sleep deprivation may be another factor to add to the list needing to be addressed in this ever rising health problem. [12] [13] [14].

Sleep deprivation elevates the circulating levels of the appetite stimulating hormone ghrelin and decreases those of leptin[15][14]. These changes could be the causes of increased food intake in those sleep-deprived adults where a rise in body weight is also observed [15]. It is therefore important to understand the health implications that sleep-deprivation, associated with jetlag and shift working, has on the body in order to develop therapeutic schemes against such related disorders as obesity.

Conclusion

Over the last decade, significant progress has been made in our understanding of the inter-relationship between circadian biology, sleep and metabolism in the context of obesity. The SCN, which is a vital coordinator of circadian rhythms, may have a role in driving feeding patterns, along with other peripheral oscillators in the brain and organs that produce rhythmic patterns in feeding time. In the modern world, sleep deprivation is a growing issue of concern and the health implications need to be acknowledged. An adequate number of hours sleep each night is vital for a healthy life. Disruptions of the circadian variations in such appetite-regulating hormones as leptin and ghrelin may contribute to the development of obesity in sleep-deprived patients. Gaps still remain in our knowledge of the underlying biological rhythms and its association with obesity. So far, therapeutic strategies have failed to curb the rising incidence of obesity, but if, through a greater understanding of these complex systems we can control appetite, the benefits will be a healthier population and less strain on the health services.

References

  1. ↑ Yi CX (2006)Ventromedial arcuate nucleus communicates peripheral metabolic information to the suprachiasmatic nucleus. Endocrinology 147:283–94
  2. ↑ Schwartz MW (2007)Central nervous system control of food intake Nature 404:661-671
  3. ↑ 3.0 3.1 3.2 3.3 Froy et al.(2010) Metabolism and circadian rhythms—implications for obesity Endocr Rev 31:1-24
  4. ↑ 4.0 4.1 Mendoza et al.(2009) Brain clocks: From the suprachiasmatic nuclei to a cerebral network. The Neuroscientist 15:5
  5. ↑ Saper A et al. (2005) The hypothalamic integrator for circadian rhythms Trends Neurosci 28:152-7
  6. ↑ Yildiz BO (2004) Alteration in the dynamics of circulating ghrelin, adiponectin and leptin in human obesity Proc Natl Acad Sci USA 101:10434-9
  7. ↑ Kalra SP(2003) Rhythmic, reciprocal ghrelin and leptin signaling: new insight in the development of obesity Regul Pept 111:1–11
  8. ↑ Kalsbeek A (2001) The suprachiasmatic nucleus generates the diurnal changes in plasma leptin levels Endocrinology 142:2677–85
  9. ↑ Gilbert J (2009) Behavioral effects of systemic transforming growth factor-alpha in Syrian hamsters Behav Brain Res 198:440-8
  10. ↑ Escobar C et al. (2009) Peripheral oscillators are important for food anticipatory activity (FAA) Eur J Neurosci 30:1665–75
  11. ↑ Pendergast et al' (2009)
  12. ↑ Gimble JM et al. (2009) Circadian biology and sleep: missing links in obesity and metabolism? Obesity Rev 10(suppl 2):1-5
  13. ↑ Rennie KL, Jebb SA (2005) Prevalence of obesity in Great Britain Obesity Rev 6:11-2
  14. ↑ 14.0 14.1 Spiegel et al.(2004) Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite Ann Internal Med 141:846-50
  15. ↑ 15.0 15.1 Taheri et al. (2004) Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index PLoS Medicine 1:e62
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