Circadian Dysfunction

7/24/2019 Circadian Dysfunction

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Circadian dysfunction in diseaseDavid A. Bechtold, Julie E. Gibbs and Andrew S.I. LoudonFaculty of Life Sciences, AV Hill Building, University of Manchester, Manchester, M13 9PT

The classic view of circadian timing in mammals empha-sizes a light-responsive master clock within the hypo-thalamus which imparts temporal information to theorganism. Recent work indicates that such a unicentricmodel of the clock is inadequate. Autonomous circadiantimers have now been demonstrated in numerous brainregions and peripheral tissues in which molecular-clockmachinery drives rhythmic transcriptional cascades in atissue-specic manner. Clock genes also participate inreciprocal regulatory feedback with key signalling path-ways (including many nuclear hormone receptors),thereby rendering the clock responsive to the internalenvironment of the body. This implies that circadian-clock genes can directly affect previously unforeseenphysiological processes, and that amid such a networkof body clocks, internal desynchronisation may be a keyaspect to circadian dysfunction in humans. Here weconsider the implications of decentralised and internallyresponsive clockwork to disease, with a focus on energymetabolism and the immune response.

Introduction Virtually all aspects of human physiology are mapped onto24-hour rhythms. These include sleep wake cycles, body temperature, hormone secretion, blood pressure, and

metabolism. These biological rhythms are orchestrated by an endogenous circadian timing system that can generaterobust and temporally relevant (i.e. 24-hour) rhythms evenin the absence of external inputs, which neverthelessremains sensitive to environmental cues such as light.Internal timers enable us to anticipate uctuations in ourenvironment and adapt our physiology appropriately. Cri-tically,the circadian clock alsosynchronizes anddictates therelative phasing of diverse internal physiological processesand molecular pathways [1]. Such internal coordinationis essential to optimise our metabolic responses andstrengthen inherent homeostatic regulatory mechanisms.

The impact of circadian timing on human health hasgarnered increasing attention over recent years, and circa-dian dysfunction is now considered to be a contributory factor to theincidenceandseverity of a wide rangeof clinicaland pathological conditions, including sleep disorders, can-cer, depression, metabolic syndrome, and inammation(Figure 1 ). Much of the initial evidence has come fromstudies demonstrating an increased association of diseasewith lifestyles that inherently disrupt our natural circadianbehavioural patterns such as chronic shift-work, frequentair travel, and chronic restriction of sleep. For example,careers involving long-term shift-work are associated with

an increased incidence of cancer of the breast and colon[24]. A direct impact of circadian timingon tumourigenesismay be envisioned because numerous genes regulating thecell cycle such as Wee1 , cyclin D1 , and c-Myc are modulatedby the rhythmic activity of core clock genes [5,6] . The clock gene period has also been implicated directly in tumoursuppression and DNA repair in rodents [7,8] , seemingly independent of its function within the clock. Discerning the relative impact of disrupted circadian rhythms per sefrom the possible pleiotropic actions of individual core clock genes in human diseasewilltherefore be a challenge.Never-theless, specic clinical indications related to altered clock functionhavebeen recognised in certaincircumstances, andare already driving therapeutic advancements. Forexample, several sleep disorders have been linked directly to altered circadian function [9] (Box 1 ).

In the current review, we briey discuss how the circa-dian clock engages with diverse physiological systemsthrough neuronal and molecular outputs. We then focuson two fundamental aspects of human physiology (energy metabolism and the immune system) to consider howdisruptions of the circadian clock may contribute to dis-ease.

Anatomy of the circadian clock

In mammals, the hypothalamic suprachiasmatic nucleus(SCN) serves as the predominant circadian timer in thebody, and is exquisitely responsive to light via the retinal hypothalamic tract. The dominance of the SCN in dictating rhythmic behaviours is demonstrated by studies of SCNtransplantation. Here, transplant of donor SCN tissue toanimals bearing SCN lesions (behaviourally arrhythmic)results in the restoration of behavioural rhythmicity whichmatches the circadian phenotype of the donor [1014] .SCN-derived signals involved in entraining locomotorrhythms are not yet fully characterised, but must includediffusible signals because encapsulated transplants canrestore rhythms to SCN-lesioned hosts. Yet, in contrast

to locomotor activity, rhythms of secretion of melatoninand glucocorticoid are not restored after SCN transplants[11 15] . Furthermore, studies of clock gene rhythms inperipheral organs show that SCN transplantation can re-establish rhythmic expression of clock genes in some per-ipheral tissues (liver, kidney), but not others (heart,spleen) [14] . Together, these ndings demonstrate that acombination of humoral factors and directneuronal contactare required for the full dissemination of SCN temporalinformation to the CNS and peripheral organs.

The neuronal projection pathways of the SCN are rela-tively well characterised, and provide the SCN accessto numerous brain regions and peripheral tissues [16] .The SCN projects heavily to other hypothalamic centres

Review

Corresponding authors: Bechtold, D.A. ( [email protected] );Gibbs, J.E. ( [email protected] ); Loudon, A.S.I.([email protected] )

0165-6147/$ see front matter 2010 Elsevier Ltd. All rights reserved. doi: 10.1016/j.tips.2010.01.002 Available online 18 February 2010 191
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[17 20] . Through such connections, the SCN is thought toimpose temporal gating to homeostatic responses of the

hypothalamus, as well as drive the rhythmic release of hormonal signals such as secretion of melatonin fromthe pineal gland. For example, circadian componentsof sleep wake cycles are driven principally throughSCN projections to the dorsomedial hypothalamus(DMN) and posterior hypothalamic area [21] . Importantly,the SCN can also access peripheral organ systems via

paraventricular nucleus (PVN) connections to the sym-pathetic and parasympathetic neural pathways [22,23] .

It has been demonstrated that the liver, the pancreas,and the visceral adipose tissue all share a common andspecic neuronal connection with the PVN, DMN, and SCN[18] . The importance of autonomic pathways in theentrainment and synchronisation of peripheral tissuesby the SCN is highlighted in studies which show thataltered outputs to peripheral organs may underlie thedamping of circadian rhythms observed in metabolic syn-drome (obesity and type-2 diabetes) [24,25] .

Work over the past decade has shown that the capacity for circadian timing is not limited to the SCN, and many other brain regions, as well as virtually all peripheraltissues can self-sustained circadian oscillation [2634] .Under normal circumstances, it is likely that theseextra-SCN clocks are subordinate to, and synchronisedby the SCN. Nevertheless, local timing systems are clearly important for individual tissue and organ function. Forexample, disruption of the clock specically within the livercauses fasting hypoglycaemia, exaggerated clearance of glucose, and loss of rhythmic expression of hepatic glucoseregulatory genes [35] . We must therefore concede thatcircadian rhythms in behaviour and physiology aredirected by a network of oscillators distributed acrossthe body. In the context of multiple body clocks, it isimportant to note that, aside from light-entrainment (of the SCN), the circadian system is highly responsive to non-photic entraining stimuli such as meal timing, exercise,

and strong social interaction.

The molecular clockThe molecular basis of circadian timing involves interlock-ing transcriptional/translational feedback loops which cul-minate in the rhythmic expression and activity of a set of core clock genes ( Figure 2 and below). Rhythmic clock genes then dictate the expression of many other genes(clock-controlled genes, CCGs), which in turn drive cas-cades of rhythmic gene expression. The impact of thesetranscriptional outputs is pronounced; gene microarray studies show that at least 10% of total cellular transcriptsoscillate in a circadian manner [32,36 40] . Interestingly, if

Figure 1 . Clocks and diseaseInappropriate or dampened circadian rhythms in behaviour and physiology can result from clock gene polymorphisms, de-synchronisation of our environment andbehaviour from our natural endogenous clocks, as well as during aging. Recent evidence suggests that disruption of the circadian system is a contributory factor to clinicaland pathological conditions including sleep disorders, cancer, depression, the metabolic syndrome, and inflammation.

Box 1. PERIOD phosphorylation: genetic disorder to drugdevelopment

A range of human sleep disorders have been linked to circadianalterations in the timing of sleep wake cycles. These disordersinclude advanced sleep phase syndrome (ASPS), delayed sleepphase syndrome (DSPS), non-24-hour sleep wake syndrome, andirregular sleep wake patterning [122] . A familial (inherited) form of advanced sleep-phase syndrome (FASPS) is characterised by apersistent and substantial ( 4 hours) advance in sleep onset andawakening times [123,124] , and was the first disorder to link aknown core clock gene directly to a human sleep disorder.

FASPS has been linked to alteration in PERIOD protein phosphor-ylation by the enzymes casein kinase 1 e and d (CK1e and d).Mutations in the PER2 (S662G), and CK1 d (T44A) genes have beenidentified in FASPS lineages [125,126] , and both are now known toalter CK1-mediated PER phosphorylation. PER phosphorylation byCK1 influences transcriptional feedback within the clock by alteringthe degradation rate and/or subcellular (nuclear) localisation of thePER proteins [125,127,128] . Thus, the molecular basis of this form of FASPS seems to be caused by an increased turnover of nuclearPER2. Similarly, the tau mutation in hamsters [129] and mice [121] ,which lies within the substrate-binding domain of CK1 e , accelerates

behavioural rhythms by 4 hours. This mutation leads to hyper-phosphorylation-mediated destabilisation of the PER proteinthrough an increase in targeted degradation [120,121,130] . Impress-ively, the 4-hour acceleration in circadian period can be observedfrom gene rhythms in single cells, to SCN and peripheral tissueoscillations, as well as in gross behavioural outputs such aslocomotor activity, metabolic rate and feeding cycles [121,130] .

These observations have driven the development of novelpharmaceutical agents that specifically target the enzymatic activityof CK1 e and d. Importantly, these agents can alter the inherentproperties of the clock (phase and period), in vitro and in vivo in adose-dependent manner [131,132] . It is tempting to speculate thatthese agents may eventually provide a therapeutic route tomodulate or strengthen endogenous rhythms, and have far-reach-ing implications for human health.

Review Trends in Pharmacological Sciences Vol.31 No.5

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different tissues are compared, there is relatively littleoverlap observed in the genes that cycle. This demon-strates that the circadian system can inuence diversephysiological processes in a tissue-specic manner.

Initially, the circadian clock was dened as a relatively

simple feedback loop based on the reciprocal interaction of activators CLOCK and BMAL1 and repressors PERIODand CRYPTOCHROME ( Figure 2 ). Within this loop,CLOCK and BMAL1 heterodimers bind to E-box enhancerelements within the promoter region of the Per and Crygenes to activate their transcription with subsequent inhi-bition of CLOCK/BMAL1 activity by PER/CRY heterodi-mers. It is now clear that the clock incorporates many auxiliary feedback loops, the most prominent of whichinvolves the nuclear hormone receptors (NRs) REV-ERBand ROR [41,42] . REV-ERB and ROR repress and activateBMAL1 expression, respectively, through shared ROR-binding elements (ROREs) within the BMAL1 promoter

[41,42] . Just as the clock feedback loops produce rhythmicoscillations in CLOCK/BMAL1, REV-ERB and ROR,similar rhythmic expression cycles are imposed onto any genes which are responsive to these transcription factorsthrough E-box, RORE and D-box (recognised by the CCG,

DBP) enhancer elements.Chromatin remodelling also appears to be an important

component in facilitating clock-regulated gene expression.CLOCK has recently been shown to function as a histoneacetyltransferase (HAT) [43,44] , and transcriptionalrhythms in gene expression can be accompanied by rhythms in histone acetylation, including within the pro-moter regions of the PER1, PER2 and CRY1 genes [45] .HAT activity (acetylation) attaches an acetyl group tothe histone, which serves to loosen chromatin structureand facilitate gene transcription. SIRT1, a protein exten-sively linked to energy metabolism and aging [46] , hasbeen identied as a histone deacetylase (HDAC) that

Figure 2 . Molecular clock machineryThe molecular machinery that provides circadian timekeeping consists of a complex circuitry of transcriptional/translational regulatory feedback loops (clock componentsshown in grey). In mammals, the current model involves a primary loop with CLOCK (or homologue NPAS2) and BMAL1 as transcriptional activators, and PERIOD (PER1,PER2 and PER3) and CRYPTOCHROME proteins (CRY1 and CRY2) as transcriptional repressors [1,119] . As levels of cytosolic PER and CRY proteins rise, they associate,translocate to the nucleus, and repress their own gene transcription through direct interaction with the CLOCK/BMAL1 complex. This feedback cycle provides near 24-hourtiming, and drives the rhythmic expression of several clock-controlled and clock-modulated genes, which in turn mediate circadian rhythms in behaviour and physiology.Acting on the primary feedback loop are auxiliary loops, which appear to increase the stability and robustness of the oscillations. The most notable interlocking loop is thatinvolving the nuclear hormone receptors (NRs), REV-ERB and ROR [41,42] . In addition to REV-ERB and ROR, several other NRs (shown in green) interact closely with thecircadian feedback loops, and are responsive to the clock (exhibit rhythmic expression) and able to feedback onto the clock genes themselves. NR regulation of clock genesalso renders the clock responsive to numerous circulating hormones (e.g. cortosol, estrogen), nutrient signals (e.g. derivatives of fatty acids and retinoids) and cellularredox status (NADH/NAD + ratio).Clock proteins are also subject to extensive post-translational modulation that serves to reinforce and fine-tune its 24-hour cycle length. For example, phosphorylation of PER proteins by casein kinase 1 (CK1) e and d isoforms has significant influence over the duration of the circadian cycle duration (period) [120,121] . Moreover, rhythms inprotein acetylation (mediated by CLOCK acetylase and SIRT1 deacetylase activities) are important in modulating the amplitude and phase of clock gene rhythms, as well asconferring circadian transcriptional regulation to clock-controlled genes [45,51 53] . BMAL1 and PER are subject to acetylation (red stars), which serves to stabilise theproteins and enhance activity. Cellular energy supply (reflected in ATP/ADP and NAD + /NADH cycles) directly influences clock activity through SIRT1 and AMPK activities.These auxiliary feedback loops and post-translational controls can modify the internal characteristics of the clock (e.g. the phase, amplitude and period of rhythmic geneexpression), making them intriguing targets for pharmacological intervention.


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counteracts CLOCK-mediated acetylation [47,48] . Targetsof CLOCK acetylation and/or SIRT1 deacetylation cyclesinclude not only histones [44] , but also clock components(e.g. BMAL1, PER2) and metabolic and inammatory regulators (e.g. PGC-1 a , PPAR a , NF- kB) [4750] . Rhyth-mic acetylation is likely to be important in modifying thestrength and phase of clock gene rhythms, as well asconferring circadian transcriptional regulation to CCGs

[45,51 53] .

Outputs of the clockThus, through transcriptional and epigenetic modulation,clock genes drive the expression of an extensive and diversesetof CCGs, which in turn drive cascades of gene expressionthat ultimately dictate rhythmic aspects of our behaviourand physiology.The rst line of CCGs directly responsive tocore clock gene regulation such as members of thePAR bZIPfamily (e.g. DBP, TEF, HLF) [54] are themselves majortranscriptional regulators. Another group of CCGs whichlink the clock to virtually all physiological processes in thebody includes members of the nuclear hormone receptor

(NR) family ( Box 2 ). Many members of this family arerhythmically regulated at the level of receptor expressionor via rhythmic ligand binding, with over half of the 48 NRgenes exhibiting rhythmic expression in a tissue-specicmanner [55] . Further, it is now evident that many NRscan modulate clock gene expression ( Figure 2 ).

Aside from their direct involvement in the clock machin-ery, REV-ERB and ROR are implicated in lipid metab-

olism, adipogenesis, and the inammatory response [5658] . Until recently, REV-ERB a and REV-ERB b were con-sidered to be constitutively active orphan receptors,although heme has now been shown to bind reversibly to both receptors and drive ligand-dependent activity [59] . This implies that REV-ERB (and in turn clock activity) are responsive to the cellular redox state andperhaps gaseous signalling molecules (NO and CO)

through interactions with heme [60] . Similarly, glucocor-ticoids and retinoic acid can synchronise and reset periph-eral clocks through their respective NRs [6163] , andPPARs, which are often rhythmically expressed in aCLOCK/BMAL1-dependent manner, can modify BMAL1expression [32,64] . PPARs bind fatty-acid derivatives, areinvolved in lipid metabolism, and are also responsive toenergy status [65] .

Consequently, NRs are not only important outputslinking the clock to most physiological processes, but alsorender the clock responsive to circulating hormones (e.g.cortisol, estrogen) and metabolic signals (e.g. derivatives of fatty acids and retinoids), as well as cellular energy and

redox status ( Figure 2 ). Interestingly, many NRs with thecapacity to alter clock function are centrally involved inenergy metabolism and the immune system. In the follow-ing sections, we consider recent evidence linking circadiandysfunction in these two physiological systems.

Circadian gating of the inammatory responseSeveral inammatory diseases exhibit a circadianelement to their symptoms. For example, patients withrheumatoid arthritis report daily variations in theirsymp-toms, experiencing greater joint pain, stiffness and func-tional disability in the mornings [66] . Some asthmapatients experience night-time exacerbations (nocturnalasthma) that can be attributed (at least in part) to daily variations in lung physiology (i.e airway narrowing), butalso increased bronchial responsiveness at night [67] .Circadian inuences on the expression and circulating level of immunomodulatory factors (hormones, cytokines)have also been documented [68] . These no doubt contrib-ute to uctuations in symptom severity, yet more intimatefeedback between the molecular clock and inammatory pathways are now being uncovered.

At this point, there is a relative paucity of data directly linking core clock proteins with inammatory pathways.Nonetheless, evidence from in-vivo studies suggest that asystemic inammatory stimulus (i.e. lipopolysaccharide(LPS) administration) canmodulate the expression of clock

genes (including per1/2 , bmal1 ) in the SCN, PVN andperipheral tissues, although some discrepancies exist be-tween studies [6971] . In addition, it has been demon-strated through microarray analysis that a group of immunoregulatory genes show a strong circadian patternof expression in the mouse liver, and this rhythmic expres-sion is lost in clock mutant mice [37] . Direct modulation of the immune response by the clock is also suggested by studies showing that the induction of pro-inammatory cytokines IFN g and IL-1 b after LPS challenge aredecreased in per2 / mice compared with wild-type mice[72] . Furthermore, polymorphisms in per3 have beenassociated with circulating levels of IL-6 [73] , and mice

Box 2. Nuclear hormone receptors

The human genome contains 48 nuclear hormone receptor (NR)genes, comprising a large family of ligand-dependent transcriptionfactors. In contrast to most classic receptors, NRs bind directly toDNA to modulate transcription, and ligand interactions occurprimarily within the cell cytosol or nucleus. NRs are key regulatorsof most major physiological processes (e.g. development, repro-duction, metabolism, inflammation and immunity), and NR ligandsinclude steroid and thyroid hormones, vitamin A and D derivatives,oxysterols, and fatty-acid derivatives. The structure of NRs isrelatively well conserved, with an amino-terminal regulatorydomain, central DNA-binding domain, and carboxy-terminal li-gand-binding domain. The receptors function as homodimers orheterodimers binding at specific hormone response elements(HSEs) within the gene promoter, and upon activation recruit co-regulatory proteins to modulate transcription. Such co-regulatorycomplexes often include proteins with intrinsic histone acetyltrans-ferase (HAT) or histone deacetylase (HDAC) activity, which repressor activate (respectively) transcription by altering the density of DNAhistone interactions. Although the mechanism remains un-clear, it is likely that NRs can also participate in non-genomicsignalling, evident by the fact that some ligand-mediated effects canbe observed within minutes of administration.

NRs are now recognised as key intermediaries between themolecular clock machinery and a wide array of physiologicalprocesses ( Figure 2 ), and two NRs, REV-ERB and ROR are bona- fide components of the clock. More than half of the NR familyexhibit rhythmic expression in a tissue-specific manner, and manycan feedback directly onto the clock itself [55,60] . For example,glucocorticoids and retinoic acid can synchroniss and resetperipheral clocks. Further, the core clock protein BMAL1 participatesin reciprocal transcriptional feedback with RORs, RER-ERBs, andPPARs. Clock NR interactions are likely to contribute to circadiandysfunction in disease, and represent targets for pharmacologicalmodulation.


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experiencing repeated phase shifts (to mimic shift-work inhumans) exhibit heightened responses to subsequentinammatory challenge [74] .

The mechanisms through which immune and inam-matory cells might be inuenced or entrained by the SCNare not presently clear, although a likely possibility is viasecretion of glucocorticoids and melatonin. Importantly,inammatory responses also appear to be gated at a local

level, within the mediating cells themselves. For example,peritoneal macrophages exhibit rhythmic clock geneexpression, are capable of autonomous gene oscillationin culture, and exhibit circadian gating in their responsesto LPS challenge [7577] . Gene microarray studies demon-strate that numerous genes involved in LPS responsepathways are rhythmically expressed in mouse macro-phages, suggesting a direct inuence of the clock on inam-matory responses [76] .

An important pathway through which the circadianclock may modify immune/inammatory responses is theNF- kB signalling cascade. The NF- kB pathway regulatesthe immune response to infection by controlling transcrip-

tion of target inammatory genes. In non-stimulated cells,NF- kB dimers are sequestered in the cytoplasm by I kBswhich mask the nuclear localisation signal; upon activation I kB is degraded to allow NF kB to enter the nucleusand activate target genes. Importantly, bmal1 knockdownin mouse peritoneal macrophages using siRNA can reducecytokine expression in concert with reduced activity of NF-kB [75] . Of note, SIRT1 has also been shown to modify theactivity of NF- kB and the release of TNF a after LPStreatment of macrophages [78] .

The impact of the clock on the immune and inamma-tory response may be indirect and involve downstreamCCGs such as the NRs. A link between NRs and inam-mation has been established. In particular, through theuse of animal models of allergic airway disease (ovalbuminchallenge) and innate airway inammation (LPS chal-lenge), ROR a , PPAR a and PPAR g have been associatedwith the pathogenesis of pulmonary inammatory diseases[79 81] . A link between REV-ERB a and the pulmonary innate immune response has also been established. Werecently demonstrated that Rev-erb a / mice exhibit aheightened inammatory response to LPS administration(signicantly increased release of specic cytokines andenhanced neutrophil recruitment to the lung) and thatapplication of a REV-ERB ligand to human alveolar macro-phages signicantly reduces the LPS-driven release of IL-6[77] . Moreover, pharmacological targeting of NRs (in-

cluding LXR and PPAR) has been successful in demon-strating their involvement in pulmonary inammation,and highlighted their potential as pharmaceutical targets.For example, the PPAR ligands fenobrate and rosiglita-zone reduce pulmonary inammation (recruitment of inammatory cells and cytokine production) after LPSadministration to mice [79,82] .

As yet, there is limited evidence to indicate the mech-anisms through which these receptors affect inammatory pathways. LXR and REV-ERB a can interact to affectexpression of the pattern recognition receptor Toll-likereceptor 4 (involved in the innate immune response)[83] , but this is the only known nuclear receptor/receptor

interaction reported to date. Several NRs are likely tomodulate the inammatory response through direct inter-actions with the NF- kB signalling pathway [80,84 86] . Forexample, experiments in human primary smooth musclecells indicate that ROR a 1 directly induces I kBa via aresponse element in its promoter [83] .

Clock dysfunction in the metabolic syndrome

Several recent studies suggest that disruption of daily metabolic rhythms is an exacerbating factor in the meta-bolic syndrome (obesity, diabetes, cardiovascular disease)[87 90] . The contribution of the circadian system in reg-ulating metabolism has received increasing attention overrecent years [9195] . Many metabolic processes exhibitcoordinated circadian oscillation, such as feeding behaviour and the metabolism of glucose and lipids [9698] ,and many genes involved in metabolic control are rhyth-mically expressed [32,33,36,99 101] . Further, shift-work and sleep deprivation are known to dampen rhythms ingrowth hormone and melatonin, reduce insulin sensitivity,and elevate circulating cortisol levels [102] . These changes

favour weight gain, obesity, and development of the meta-bolic syndrome. The importance of a functional circadiansystem in the regulation of metabolism is also evident fromstudies of animals with disrupted clock gene expression orfunction [103 106] . Forexample, clock mutant mice exhibita reduced metabolic rate and obesity [103] .

Metabolic processes are readily decoupled from theprimarily light-driven SCN when food intake is desynchro-nised from normal daily patterns of activity. This has beenextensively modelled in rodents using restricted feeding schedules (RFS) [107,108] . Under RFS, numerous physio-logical and metabolic functions become entrained to theavailability of food, e.g. locomotor activity, insulin andcorticosterone release. Therefore, rhythmic feeding appears to be the dominant Zeitgeber for peripheral circa-dian oscillators [31] , presumably to ensure optimal syn-chrony between metabolic processes and food intake. Forexample, clock gene rhythms in the liver can entrain toRFS within two days even though SCN activity remainslocked to light dark cues throughout the duration of RFS[109] . This implies that internal de-synchronisation(decoupling of peripheral clocks from the SCN) could resultfrom lifestyles that oppose natural circadian rhythms.Scheer and colleagues recently examined the effects of such internal de-synchrony in humans by placing subjectson a 28-hour daily routine for 10 days [110] . Similar toobservations made using animal models, rhythms in body

temperature remain tied to a 24-hour cycle; while others(such as leptin and insulin) adhered to the new 28 hour-based cycles of food intake. Interestingly, circadian (24-hour) and behavioural (28-hour) misalignment caused asuppression of circulating leptin, an elevation of bloodglucose, and hypertension. Therefore, similar to changesobserved with chronic sleep deprivation [102] , misalign-ment triggers a perceived state of energy decit, alteredglucose homeostasis, and decreased insulin sensitivity, allof which predispose to the metabolic syndrome. Sleeprestriction can also increase levels of the orexigenic hor-mone ghrelin, which has been strongly implicated in foodanticipation and meal entrainment [111] .


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The mechanisms involved in clock entrainment to meta-bolic signals remainunclear. The direct inuence of cellularenergy and redox status on clock genes has been demon-strated. For example, the activities of CLOCK/BMAL1 andSIRT1 areresponsive to the intracellular ratio of reduced-to-oxidized nicotinamide adenine dinucleotide (NAD) cofac-tors, a ratio which is closely tied to cellular energy metab-olism [97,112,113] , and uctuations in glucose itself can

modulate and entrain circadian oscillations in cells grownin culture [114] . Further, as mentioned above, the clock machinery is responsive to several genes which are them-selves responsive to cellular and global energy status, in-cluding SIRT1, the PPARs, and PGC-1 a . Feedback fromthese genes would therefore render the clock responsive tometabolic cues ( Figure 2 ). The PPARs and PGC-1 a regulategenes involved in many aspects of energy homeostasis,including the metabolism of glucose and lipids [115,116] ,andtheirexpressionsand activities areresponsive to energy status and feeding cues [65] . In mice, PGC-1 a is rhythmi-cally expressed, and stimulates bmal1 and REV-ERB atranscription through association of ROR a [117] . Pgc-

1a

/

mice display metabolic and circadian abnormalities,including altered weight gain, muscle dysfunction, hepaticsteatosis, as well as altered daily rhythms of activity, body temperature, and metabolic rate [115,117] . Interestingly,PGC-1 a knockout mice appear to have a reduced ability tophase-reset liver clock gene expression in response to a shiftfrom night-restricted to day-restricted feeding [117] ,suggesting that feedback between PGC-1 a and core clock genes may be required for optimal entrainment of periph-eral clocks to energy-related cues.

The sensitivity of different body clocks to metabolicinput may be dictated to a great extent by the local(tissue-specic) expression of energy-responsive genes(e.g. PPAR a , PGC-1 a , SIRT1). Therefore, imposition of chronic and inappropriate metabolic inputs onto the clock through metabolic regulators such as PGC-1 a might con-tribute to damping of metabolic rhythms observed inobesity. Additionally, the uncoupling of peripheral circa-dian oscillators like those in the liver from the SCN during altered energy status raises the distinct possibility thatabnormal energy supply (including unrestricted hyper-caloric food intake and feeding schedules that are outof synchrony with normal patterns of behaviour) may beeffective at dampening the hypothalamic control of metab-olism. Therefore, therapeutic strategies aimed at strength-ening clock synchrony, minimising periods of internal de-synchrony experienced during repeated behavioural phase

shifting (shift-work), and reinforcing circadian rhythms inpatients with metabolic syndrome should be pursued.

Future perspectivesCircadian dysfunction is clearly linked to human patho-physiology whether as a contributing factor or con-sequence. Nevertheless, clinical implications of clock gene polymorphisms and mutations have been identiedand are driving the development of novel therapeutics. Thechallenge remains to determine what impact the disrup-tion of circadian rhythms per se has on disease states suchas cancer and the metabolic syndrome, rather than thepleiotropic effects of clock genes independent of their role

in circadian timing. Nevertheless, targeting the circadianclock as a mechanism for strengthening inherent homeo-static and defence mechanisms would seem an importantand potentially fruitful therapeutic aim. Key sites fortherapeutic targeting include primary CCGs, particularly those capable of feeding back onto the clock (i.e. NRs), aswell as clock-associated enzymes such as CK-1, AMPK, andSIRT1. Several pharmaceutical tools have recently been

developed which target all three enzymes [118] , and it willbe interesting to see if these agents may be useful inmodulating clock activity in vivo .

Disclosure StatementDAB, JEG, and ASIL have no conicts of interest relating to the content, writing or publication of this work. Ourwork is supported by the Biotechnology and BiologicalSciences Research Council (BBSRC), UK.

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