Review series

Circadian rhythms, sleep, and metabolism

Wenyu Huang,1,2 Kathryn Moynihan Ramsey,1,2 Biliana Marcheva,1,2 and Joseph Bass1,2
1Department 2Department

of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA. of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, USA.

The discovery of the genetic basis for circadian rhythms has expanded our knowledge of the temporal organization of behavior and physiology. The observations that the circadian gene network is present in most living organisms from eubacteria to humans, that most cells and tissues express autonomous clocks, and that disruption of clock genes results in metabolic dysregulation have revealed interactions between metabolism and circadian rhythms at neural, molecular, and cellular levels. A major challenge remains in understanding the interplay between brain and peripheral clocks and in determining how these interactions promote energy homeostasis across the sleep-wake cycle. In this Review, we evaluate how investigation of molecular timing may create new opportunities to understand and develop therapies for obesity and diabetes.
Introduction: circadian clocks and metabolism from molecular systems to physiology Studiesinplantsdatingfromthe18thcenturyoriginallyestablishedthat24-hourperiodicphenomenaarisefrombiological oscillatorsthatinternallytracktherotationoftheEarth.These so-called circadian clocks (the term is derived from circa diem,oraboutaday)areentrainedbylightandsynchronizeenergy-harvestingandutilizationprocesseswiththerising andsettingofthesun(ref.1andFigure1A).Atthemolecular level,circadianrhythmsareencodedbyanautoregulatoryloop composedofasetoftranscriptionactivators(CLOCK:NPAS2/ BMAL1[MOP3])thatinduceexpressionofrepressors(PER13/ CRY12)thatfeedbacktoinhibittheforwardlimb.Discoveryof thismechanismstemmedfromdeliberatemutagenesisexperimentsinflies(2),andforwardgeneticsinmiceultimatelyled tothediscoveryofthefirstmammalianClockgene(35).Subsequentworkhasrevealedthatthemammalianmolecularclockis notonlyexpressedwithinthemastersuprachiasmaticnucleus (SCN)pacemakerneurons,butalsowithinnearlyallcells(6,7). In addition to this core loop, CLOCK/BMAL1 also induce expressionoftheorphannuclearhormonereceptors(NHRs) RORandREV-ERB,whichactivateandrepressBmal1transcription, respectively. Posttranslational regulation of clock transcriptionfactorsbycaseinkinaseIandI(CKI/),-TrCP, FBXL3,andARF-BP1/PAM,inadditiontocAMPsignaling(8), furthermodulatescircadianoscillations(1).Thepurposeofthis Reviewistoprovideanoverviewofthegeneticandneurobiologicalevidencelinkingcircadianandenergeticsystemsandto highlightgapsinourunderstandingofthemolecularpathways thatcoupletheseprocesses. Neural networks linking circadian and energetic centers Invertebrates,circadiansystemsareorganizedhierarchically withmasterpacemakerneuronswithinthehypothalamicSCN presidingoveradistributednetworkofextra-SCNandperipheralclocks(9).Theenvironmentallight-darkcycleprovidesthe principalentrainingsignaltotheSCN,whichinturnproduces synchronizedrhythmsofbehaviorandphysiologythroughalignmentofcircadiangeneoscillationwithinbothextra-SCNneuConflict of interest: JosephBassisamemberofthescientificadvisoryboardofReSet TherapeuticsInc.andhasreceivedsupportfromAmylinPharmaceuticals. Citation for this article:J Clin Invest.2011;121(6):21332141.doi:10.1172/JCI46043.

ronsandperipheraltissues(Figure1B).Wiringoftheneural circuitgeneratingcircadianrhythmsinvolvesprojectionsofthe SCNtoawiderangeofcellbodieswithinboththehypothalamus (includingthearcuatenucleus[ARC],paraventricularnucleus [PVN],lateralhypothalamicarea[LHA],anddorsomedialhypothalamus[DMH];refs.1016)andthebrainstem(includingthe ventraltegmentalarea[VTA]anddorsomedialnucleusofvagus [DMV]viarelayatthemedialpreopticarea[MPO]andPVN, respectivelyrefs.17,18)(Figure2).WithintheARC,neurons expressing orexigenic neuropeptide Y/Agouti-related protein (NPY/AgRP)andanorexigenicpro-opiomelanocortin/cocaine- andamphetamine-regulatedtranscript(POMC/CART)peptides formreciprocalconnectionswithcellslocatedwithintheSCN (10,11).Inaddition,NPY/AgRP-andPOMC/CART-expressing neuronsandSCNneuronsprojecttocellbodieswithinthePVN andLHAthatmodulateautonomic(18)andsleep-wakefulness (19,20)behavior,respectively.Whilepeptidergicsignalingwithin NPY/AgRPandPOMC/CARTneuronshasbeenshowntoinfluencelong-termbodyweightconstancy(seerefs.2124formore completereviews),lessisknownconcerningcircadianmodulationofsignalingwithinthesecells.Forinstance,clockgenesare expressedcell-autonomouslywithincellbodiesthatreceiveprojectionsfromtheSCN;thusitispossiblethatoscillationofkey transcriptsimportantintheresponsetoanorexigenicandorexigenichormonesmaybesubjecttocircadiancontrol.Interestingly, feedinganisocalorichigh-fatdietattheincorrectcircadiantime hasbeenshowntoresultinincreasedweightgaininmice(25), suggestingthatcircadianalignmentoffeedingandactivityiscriticalinthehomeostaticcontrolofbodyweight.ItisalsointriguingthatprojectionsoriginatingintheSCNdirectlysynapseatthe orexin-producing(ORX-producing,alsoreferredtoashypocretinproducing)neuronswithintheLHA(14,26,27).ORXneurons intheLHAareimportantinperipheralglucosemetabolism(28) andalsoparticipateinlong-termweighthomeostasis,sinceORX receptorknockoutmicearesusceptibletodiet-inducedobesity (29).Finally,sincedopaminergicsignalingintheVTAneurons isimplicatedinrewardsystemsassociatedwithfeeding(30,31), anintriguingquestioniswhetherhedonicdrivemightsimilarly displaycircadianvariation(32).Furtherstudiesareneededto definetherepertoireofconnectionsbetweenSCNandenergetic neurons,todeterminetheimpactoffeedingrhythmsonfunction andentrainmentofextra-SCNclocks,andtoelucidatehowclocks participateinmelanocortinergicanddopaminergicsignaling.
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Figure 1
Circadian control of energy metabolism. (A) In plants, cyanobacteria, and fungi, energy is available during the light period within the light/dark cycle, while in metazoa, alternating periods of sleep and wakefulness, closely associated with the light/dark cycle, impart cyclicity on feeding behavior and fuel utilization. (B) The master clock in the SCN sends signals to the extra-SCN regions, which in turn entrain peripheral tissues via hormonal, autonomic nervous system (ANS), and behavioral pathways in order to regulate peripheral clock control of fuel utilization and energy harvesting. Extra-SCN regions also regulate energy homeostasis by controlling cyclic energy intake and locomotor activity. Through regulation of food intake, physical activity, and metabolic processes, both brain and peripheral clocks contribute to long-term weight stability by maintaining a precise balance between energy intake and energy expenditure. A positive energy balance deposits stored energy mostly into adipose tissue, leading to obesity, while a negative energy balance results in leanness. BMR, basal metabolic rate.

Interaction of circadian and metabolic systems at the cell and molecular levels Integrationofcircadiansystemswiththelight/darkenvironment involvesawidelydistributednetworkoflocaltissueclockswithin boththebrainandperiphery(3336)(Figure3).Interestingly,a varietyoffactorsincludingfoodavailability,glucocorticoidlevel, andtemperature,socalledzeitgebers(timegivers),areable toresetthephaseofperipheralclocks.Incontrast,theSCNis entrainedonlytolightbutnottofeeding;thusshiftsinfeeding timeuncouplethephaseofperipheraltissueclocksfromthatof theSCN(3740). Feedback loops between nutrient sensors and molecular clocks in peripheral tissues (NAD+, NAMPT, SIRT1, AMPK).Recentstudieshavedemonstratedthatvariousnutrientsensorsareabletorelayinformation regardingthecellularnutrientstatustothecircadianclock.For example,earlystudiesindicatedthatthereducedformsoftheredox cofactorNADHincreaseCLOCK/BMAL1andNPAS2/BMAL1 heterodimeractivity,whereastheoxidizedforms(NAD+)inhibittheiractivity(41).TheNAD+-dependentdeacetylasesirtuin1 (SIRT1),whichisinducedbyacutenutrientwithdrawal(42)or calorierestriction(43),alsodirectlybindstotheCLOCK/BMAL1 complextoregulateexpressionofclockgenes(4447).AMPkinase (AMPK)servesasanotherhighlyconservedcellularnutrientsensorthat,whenactivatedbyexercise,fasting,orhypoxia(48),leads to phosphorylation and degradation of CRY1 (49), as well as activationofNAMPT,therate-limitingenzymeinNAD+salvage biosynthesis(50).Interestingly,theconnectionbetweennutrient sensorsandmolecularclocksisbidirectional.LevelsofNAMPT, aswellasNAD+itself,exhibitcircadianoscillations,andNampt
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genetranscriptionisdirectlyregulatedbyCLOCK(46,47).As such,SIRT1activityisindirectlyregulatedbytheclocknetwork. Together,thesedatademonstrateonamolecularlevelthatthere isacomplexcrosstalkbetweenhighlyconservednutrientsensors andthemolecularclocknetworks,atleastatthelevelofperipheral tissues(seebelowfordiscussionregardingpotentialrolesofCNS nutrientsensorsincircadiancontrolofmetabolism). Metabolic transcription factor and transcriptional co-activator feedback on the core clock in peripheral tissues (REV-ERB, ROR, PPAR, DBP, PGC1).NHRsareligand-activatedtranscriptionfactors,a majorityofwhich,includingREV-ERB,RORsandPPARs,demonstratecircadianexpressioninperipheraltissues(51).REV-ERB regulateshepaticgluconeogenesis,adipocytedifferentiation,and lipidmetabolism,andalsorepressesBmal1transcription(52,53). RORcompeteswithREV-ERBinbindingtotheBmal1promoterandinducesBmal1expression(54)inadditiontoregulatinglipidmetabolism(55).PPAR,whenactivatedbyendogenous fattyacids(FAs),stimulatesFAoxidation,regulatesgenescontrollinglipidhomeostasis,andpreventsatherosclerosis(56).Inaddition,PPARpositivelyregulatesBmal1expression,whileBMAL1 likewiseactivatesPPAR,generatingapositivefeedbackloop(57). Anothersubtype,PPAR,playsanimportantroleinadipocytedifferentiationandtriglyceridesynthesis(58).PPARinducesBmal1 expressioninthebloodvessels,andvasculature-specificPPAR knockoutleadstomarkedreductioninthecircadianvariationin bloodpressureandheartrate(59). InadditiontoNHRs,Dbp,aknownclocktargetgene,regulates expressionofkeymetabolicgenesinvolvedingluconeogenesisand lipogenesis(60).BecauseDBPlevelschange100-foldinresponse

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Figure 2
Map of neural circuits linking SCN and extra-SCN regions important in circadian and energetic control. CNS centers receive dual input of light and metabolic signals. Light reaches the SCN via the RHT, which in turn sends neural projections to various extra-SCN regions in the hypothalamus and brainstem that are critical for energy homeostasis and sleep, including the ARC, PVN, and ventrolateral preoptic nucleus (VLPO). The hypothalamus also receives metabolic inputs, including peptidergic hormones and nutrient metabolites, which modulate the CNS signaling. Thus signals from the exogenous environment (i.e., light) and endogenous metabolism (i.e., metabolic cues) are integrated in the CNS, the output of which in turn imparts rhythmicity on sleep and a variety of metabolic outputs, such as thermogenesis, feeding behavior, hormone secretion, and locomotor activity. IML, intermediolateral nucleus; NTS, nucleus tractus solitarius. dSPZ, dorsal subparaventricular zone; RHT, retinohypothalamic tract; vSPZ, ventral subparaventricular zone; MCH, melanocyte concentrating hormone.

toCLOCK/BMAL1activation,itisconceivablethatDBPgeneratescircadianoscillationinmetabolicprocessessuchasgluconeogenesis.Additionally,thetranscriptionalco-activatorPPAR co-activator1(PGC-1)(61)alsodisplayscircadianoscillations andregulatesBmal1andRev-erbaexpression.KnockoutofPgc1a leadstoabnormaldiurnalrhythmsofactivity,bodytemperature, andmetabolicrate,inadditiontoaberrantexpressionofclock andmetabolicgenes(62).Interestingly,SIRT1suppressesPPAR (63)butactivatesPGC-1(64),andthusaffectstheclocknetwork throughmultiplemechanisms. Possible molecular integrators of circadian and metabolic systems in the CNS.Molecularanalysesofinterplaybetweencircadianandmetabolicpathwayshaveprimarilyemergedfromstudiesinliverand otherperipheraltissues,yetitremainsuncertainwhethersimilar mechanismsmightalsocoupletheseprocesseswithinthebrain. Onequestioniswhetherspecificmetabolitesthatvaryaccordingto timeofdayandnutrientstate(fastingvs.feeding),mayalsoaffect

circadianfunctionofenergy-sensingneurons.Forinstance,24-hour oscillationinlevelsofglucoseandFAsmayinturninfluenceexpressionofcircadiangenesandrhythmictranscriptionaloutputswithin hypothalamicneuronsinvolvedinglucosehomeostasis(65),food intake(66),andenergyexpenditure(6770).Perturbationofmetabolichomeostasiswithahigh-fatdietissufficienttoalterbothperiodlengthandamplitudeoflocomotoractivity(71).TheseobservationsindicatethatchangesinFAmetabolismpersemayeitheralter clockgenefunctionwithinSCNpacemakerneuronsand/orinterruptcommunicationbetweenSCNandextra-SCNneurons. Additionalnutrientfactorsthatmayparticipateincircadian oscillations of SCN and extra-SCN neurons include AMPK, SIRT1,andthemammaliantargetofrapamycin(mTOR).HypothalamicAMPKisregulatedbynutrientstateandhormones suchasleptinandinsulin(72),andmanipulationofitsexpressionaltersfoodintakeandbodyweight(73);howevertheimpact ofAMPKonCNScontroloflocomotorbehaviorandphysiologi2135

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Figure 3
Interactions between the molecular clock and downstream metabolic genes. The core molecular clock consists of several transcription/translation feedback loops, including posttranscriptional regulation (yellow), that oscillate with an approximately 24-hour periodicity. CLOCK and BMAL1 heterodimerize to drive rhythmic expression of downstream target genes (shown in red), which in turn regulate diverse metabolic processes, including glucose metabolism, lipid homeostasis, and thermogenesis. Many of these clock target genes in turn reciprocally regulate the clock in response to changes in nutrient status (shown in blue) via cellular nutrient sensors (shown in orange), generating a complex network of interlocking feedback loops that fine-tune the clock and coordinate metabolic processes with the daily cycles of sleep/wakefulness and fasting/feeding. Dashed lines represent metabolic inputs; solid lines depict interactions among core clock genes, clock-controlled genes, and nutrient sensors.

calrhythmsisstillnotknown.NPYandPOMCneuron-specific knockoutofthe2subunitofAMPKresultsinleanandobese phenotypes,respectively,soitwillbeinterestingtolearnwhetherAMPKalsoparticipatesinsynchronizingactivityandfeeding throughactionswithinthesecellgroups(74).SIRT1mayalso representanadditionalmechanismcouplingnutrientfluxwith rhythmicactivityofhypothalamicneurons,asthenutrient-sensingdeacetylaseispresentwithinbothARCandDMH/LHAneurons(75,76).Afinalpotentialmediatorinvolvedinbothenergy sensingandcircadianfunctionintheCNSismTOR,aregulatorofproteinsynthesispresentinARCneuronsthathasbeen showntomodulatefoodintake(77).mTORisalsoexpressed withinpacemakerneuronsoftheSCN,whereitsexpressionis

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activatedbylight(78).Moreover,activationofmTORcauses phaseresettingofSCNexplants(79),whileinhibitionofmTOR alterslightinductionofthePeriodgenewithintheSCNofthe intactanimal(78).Thusaminoacidmetabolismmayparticipate inbothentrainmentofthemasterclockandinthetemporal organizationoffeeding. Nutrientsignaling,whetherthroughglucose,FAs,AMPK,SIRT1, ormTOR,mayfunctiontoentrainorgateCNSandperipheral clocks,leadingtotissue-specificdifferencesinphaseandamplitudeofgeneexpressionrhythms.Indeed,differentzeitgebersmay exertdifferingeffectsoncircadianentrainmentinthebrainand peripheraltissues,leadingtodistincteffectsonphaseandamplitudeofgeneoscillationwithintheselocales.Itisalsopossiblethat

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entrainmentofperipheralclocksbyspecifichormonesmaybe phasedependent(80);thatis,localtissueclocksmayonlyrespond tophase-resettinghormonesand/ormetaboliteswhentheseare presentwithinanarrowwindowoftimeduringthe24hourlight/ darkcycle.Forinstance,glucocorticoidsecretionfromadrenal glandsinresponsetoadrenocorticotropinisdependentontime ofday(81).Inadditiontometaboliteandhormonalinputinto theclock,recentstudiesbyBuhretal.suggestthattemperature andheatshocksignalingpathwaysplayacentralroleinentrainmentofperipheraltissues(39).Importantly,sincealterationin temperatureand/ortheheatshockpathwayiscloselyassociated withothersynchronizingsignalsincludingfeedingandglucocorticoidsecretion,itmayserveasaunifyingsignalinentraining peripheralclocks.Amajorobjectiveinfutureresearchwillthusbe todelineatetheroleofnutrientsignalinginentrainmentofCNS andperipheralclocks,andtodeterminehowthesesignalsinteract withsynchronizingsignalssuchasfeedingandneuroendocrine hormones(e.g.,glucocorticoids)tomaintainphasealignmentof behavioralandmetabolicrhythmswithinthewholeorganismat thelevelsofbothphysiologyandpathophysiology. Role of the circadian system in energy balance, metabolism, and sleep Evidence for circadian integration of energetics, metabolism, and sleep in humans.Inhumans,manyaspectsofmetabolismdisplaycircadian cycles,including24-hourvariationofglucose,insulin,andleptin levels(82,83).Genome-wideassociationstudieshavealsosuggestedconnectionsbetweenclockgenevariationandfastingglucose levels(84,85),obesity,andmetabolicsyndrome(86),raisinginterestinunderstandingtheimpactofcircadiansystemsonhuman disease.Onecommonclinicalconditionsuggestiveofinteractions betweencircadianrhythmsandmetabolisminhumansisthatof shiftwork.Numerousreportshaveindicatedthatshiftworkers haveahigherincidenceofdiabetes,obesity,andcardiovascular events(1,87),althoughthemechanismunderlyingthisassociation isuncertain.Scheeretal.recentlytestedtheimpactofforcedcircadianmisalignment(asimulationofshiftwork)onneuroendocrine controlofglucosemetabolismandenergetics(88).Inparticipants subjectedtocircadianmisalignment,theinvestigatorsobserved hypoleptinemia,insulinresistance,invertedcortisolrhythms,and increasedbloodpressure(88).Itisalsointerestingtonotethat patientswithdiabetesexhibitdampenedamplitudeofrhythmsof glucosetoleranceandinsulinsecretion(89);thustherelationship betweencircadiandisruptionandmetabolicpathologiesappears tobebidirectionalinhumans,suggestingthatcircadiandisruptionmayleadtoaviciouscycleandcontributetoaugmentation andprogressionofmetabolicdisease. Directgeneticevidenceinhumanshaslinkedthemolecularclock withsleep(90,91)throughthepositionalcloningofmutations causingfamilialadvancedsleepphasesyndrome,whichischaracterizedbyearlysleeponsetandawakening(92).Inthegeneral population,observationalstudieshavealsofoundthatshortsleep, sleepdeprivation,andpoorsleepqualityareassociatedwithdiabetes,metabolicsyndrome(82,93),hypoleptinemia,increasedappetite,andobesity(94,95).Arecentstudyshowedthatsleepduration correlateswiththemagnitudeofweightlossasfatinresponseto caloricrestriction;shortsleepersappeartohavemoredifficultylosingfatcomparedtolongsleepersdespitesimilaramountofweight loss(96).Narcolepsy,asleepdisorderinwhichpatientspresentwith extremedaytimesleepinessduetolossofhypocretin-producing

neurons(97,98),hasbeenassociatedwithelevatedBMI(99)and increasedincidenceofobesity(100,101).Nighteatingsyndrome (NES)isanotherinstanceinwhichdisruptedrhythmicpatternsof sleepandeatingcorrelatewithalteredmetabolism(102)andobesity(103).PatientswithNESconsumesignificantlymoreoftheir dailyenergyintakeatnight,althoughtheirtotaldailyfoodintake issimilartothatofcontrolsubjects(104,105).Theyalsohave abnormalrhythmsofmetabolichormones,includingdecreased nocturnalriseinleptin,aphaseshiftininsulin,cortisol,andghrelin,andinverted24-hourrhythmsofbloodglucose(104,106). Interestingly,thenocturnalpatternofeatingobservedinNES patientsisreminiscentoffeedingalterationsintheClockmutant mouse.Theseanimalsexhibitincreasedfeedingduringthenormal sleepperiodtogetherwithincreasedsusceptibilitytodiet-induced obesity(107).Amajorgoalistodeterminewhethertheadverse metabolicconsequencesofsleeploss(andaccompanyingfeeding alterations)areduetothedisruptedcircadianrhythmsperse,to thealteredsleep,ortosomecombinationofthetwo.Nonetheless, theaboveobservationsinhumansdemonstratethatsynchronizationoffeeding/fastingandactive/restperiodswiththeenvironmentallight/darkcycleinfluencesbodyweightconstancy. Integration of circadian rhythms and energy homeostasis in animal models. Studiesinrodentshavealsoattemptedtoexperimentallysimulate shiftworkinordertofurtherprobemechanismslinkingcircadian disruptionwithmetabolicdisorders.Whenratswereexposedto adailyeight-houractivityscheduleduringtheirnormalresting phase,theysuccumbedtodiminishedrhythmsofglucoseandlocomotoractivity,aswellasobesity,whichcorrelatedwithincreased foodintakeduringtheirrestingphase(108).However,shiftingfood intakebacktotheactivephaserestoredtheirmetabolicrhythms andpreventedobesityinthesesameanimals(108),suggestingthat thenormalalignmentoffeedingandactivitywiththeenvironment lightcycleiscriticalforthemaintenanceofenergyhomeostasis. Furthermore,feedingwild-typemiceadlibitumexclusivelyduringthedaytimeresultedingreaterweightgainthaninanimalsfed exclusivelyatnight(25).Similarly,whengeneticallyobesemicewith disrupteddiurnalfeedingpatternswerefedexclusivelyatnight, theirobesityandmetabolicdisordersimproved(109). Geneticanimalmodelsofclockgenedisruptionhaveprovided anadditionalapproachtospecificallydissecttheeffectsofmolecularclockgenesonenergyhomeostasis.Forexample,Clockmutant miceareobeseandhyperphagic(107),althoughthisphenotype maybemodifiedbygeneticbackground(110).Moreover,introgressionoftheClockmutationintotheob/obstrainexacerbates obesity(111).Inadditiontocausingmetabolicdisorders,both ClockmutantandNpas2/micedisplayabnormalitiesinsleep architecture,soitwillbecriticaltodeterminethecause-and-effect relationshipbetweenalterationsinsleepandfeedinginthese models(112,113).Inaddition,Npas2/micedisplayincreased activityduringthesiestathatwild-typemicenormallytakeduringthemid-activeperiod(112).Incontrast,Clockmutantshave increasedlocomotoractivityandfoodintakeduringtheperiod whenwild-typemiceareatrestandfasting(107),suggestingnonredundantfunctionsbetweentheClockandNpas2paralogswith regardtoenergybalance.GlobalBmal1knockoutmicearearrhythmicanddisplayincreasedadiposityatearlyages(114);however, theseanimalsalsodeveloparthropathyandmyopathy,resultingin decreasedactivityandweight(115).Interestingly,brainrescueof Bmal1-knockoutmiceonlyrestoresbehavioralcircadianrhythms, whereasmusclerescuerestoresactivitylevelsandbodyweight,but
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notbehavioralrhythms(116,117),suggestingthatBMAL1functionwithinthebraincontrolsperiodlengthandactivityrhythms, whereasitsexpressioninmuscleaffectsmitochondrialfunction andexercisetolerance(117).Curiously,micewithmutationsin thePeriodgenesdisplayincreasedadiposity(118).Futureapplicationofneuron-specifictargetingapproacheswillbeimportantto identifyselectiveeffectsofcircadiangenedisruptionontheinterrelationbetweensleepandenergyhomeostasis. Integration of circadian rhythms and glucose homeostasis in animal models. Glucosehomeostasisisundercircadiancontrolatthelevelofboth peripheraltissuesandtheSCN.Adlibitumglucoselevelspeakand glucosetoleranceisenhancedatthebeginningoftheactivephase comparedwiththerestphase(119,120).Themorningpeakofglucoseispostulatedtoresultfromincreasedhepaticgluconeogenesis (120)aswellaslowinsulinsecretion(121),whereastheimproved glucosetolerance(earlyintheactiveperiod)islikelyduetoelevated glucoseuptakeatskeletalmuscleandadiposetissues(119,122). Geneticdisruptionofcomponentsoftheclocknetworkhasidentifiedaroleofcoreclockgenesinglucosehomeostasis.Forexample, multi-tissueClockmutantmicedevelopage-dependenthyperglycemiaandhypoinsulinemia(107,123),inpartduetoimpaired insulinsecretionanddefectsinproliferationofpancreaticislets. Cry-knockoutanimalshaveincreasedhepaticgluconeogenesis,in partduetoupregulationofcAMPsignaling(124).Amajoradvance towardunderstandingthetissue-specificrolesofperipheralclocks inglucosehomeostasiscamewiththedevelopmentofconditional gene-targetingapproaches.WhiledeletionofBmal1withinliver causeshypoglycemia(114),deletionofBmal1withinpancreas causeshyperglycemiaandhypoinsulinemia(123);thusatthephysiologicallevel,theactionsofclockactivatorgenesintheliveroppose thoseinthepancreas.Interestingly,bothClockmutantandBmal1knockoutmicearehypersensitivetoinsulin,althoughthemechanismforthisremainstobedefined(115).Whiletheabovegenetic modelsdemonstratearoleforperipheralclocksinregulationof glucosemetabolism,theSCNalsoplaysacriticalroleincontrollingthecircadianvariationofglucoseandglucosetolerance(119), inpartthroughrhythmicmodulationofautonomicnervoussystemefferents(125).Animportantremainingquestioniswhether peripheralclocksarenecessaryfortheproperalignmentofbehavioralstates(sleep/wakefulness,fasting/feeding)withperipheral metabolisminliver,muscle,adiposetissue,andpancreas. Integration of circadian rhythms and lipid homeostasis in animal models. Inadditiontoglucoregulatorypathways,thecircadiansystem alsoregulateslipidhomeostasisandadiposetissuemetabolism. Bothintestinallipidtransportanddenovolipidsynthesisexhibit circadianvariation(126),asdolevelsofadiposetissuehormones suchasadiponectin(127)andleptin(128).Hypertriglyceridemia isevidentinClockmutantmice(107),likelyduetobothintestinal overabsorption(129)andhepaticoverproduction(130).Onenode ofcouplingcircadianandlipogenicpathwaysinvolvesREV-ERB (52).REV-ERBcontrolsSREBPsignalingandbileacidhomeostasis,bothofwhichareessentialforlipidmetabolism(131). Furthermore,BMAL1isnecessaryforadipogenesis,asembryonic fibroblastsfromBmal1knockoutmicefailtodifferentiateintoadipocytes(132).ClockgenesmayalsoindirectlyregulateadipogenesisviaPPARs.Finally,theSCNhasalsobeenshowntobecritical forregulationofthediurnalityofleptinrelease(133,134).Further studiesarenecessarytoassessthepotentialimpactofclockgenes onadditionalfunctionsoftheadipocytes,includingthermogenesisandlipokinesecretion.
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Reciprocal effects of nutrient signaling on circadian rhythms and sleep. Therelationshipbetweencircadianrhythmsandmetabolismis bidirectional;asnotedabove,ahigh-fatdietlengthenstheintrinsic periodlengthoflocomotoractivity,altersthecircadianrhythmsof feeding,reducestheamplitude,andshiftsthephaseofmetabolic geneexpressioncyclesinliver,fat,andhypothalamus(71).Similarly,geneticallyobeseob/obanddb/dbmice(135,136)havedisrupted circadianrhythmsofactivityandsleep/wakepatterns.Inaddition, glucocorticoid,ametabolichormoneinvolvedinnumerousbiologicalprocessessuchasgluconeogenesis,alsoentrainsperipheralclocks(40)andincreasesexpressionofmultipleclockgenes, includingPer1andPer2(137). Restrictedfeedingstudieshavefurthersuggestedthatnutrient conditionsinfluencerhythmiclocomotoractivityandperipheral clockgeneentrainment,althoughtheroleofclockgenesperse inactivityrhythmsremainscontroversial.Whereastheperiodof locomotoractivityprogrammedbytheSCNremainsconstant evenwhenfoodisrestrictedeachdaytothelightperiod,foodrestrictedanimalsdisplayananticipatoryincreaseinlocomotor activity(138),temperature,andglucocorticoidsecretionthatpersistsevenwhenthefoodisremoved(139).Moreover,foodavailabilitycanentrainrhythmsinperipheraltissuessuchasliverand kidney,butnotintheSCN(37,38),suggestingtheexistenceof afood-entrainableoscillator(FEO)(140).Theanatomiclocation oftheFEOhasbeenatopicofintensiveinvestigation,although effortstounderstandthemechanismforthisprocesshaveproducedinconclusiveresults.Whileseveralstudieshavesuggested thattheDMHisnecessaryandsufficienttoinducefood-entrainablecircadianrhythms(141,142),otherstudieshavequestioned theroleoftheDMHastheFEO(143). Animportantremainingquestionconcernstheidentityofthe synchronizingsignalsthatadjustcircadianoscillationsaccording tofeedingtime.Potentialsignalsinvolvedinresettingperipheral clocksarenumerous,includingglucose,lipids,sterols,peptidergic molecules,andcatecholamines.Elucidatingmechanismsinvolved incircadianentrainmentoffeedingmayleadtoimprovedinterventionsforclinicalpathologiesassociatedwithshiftworkandjetlag. Concluding remarks Advancesingeneticstudiesofcircadianrhythmshaveledto the recognition that the circadian system is tightly coupled withprocessescontrollingbothsleepandmetabolism.These dynamicinteractionsensurethatenergymetabolismiscoordinatedinapropertemporalpatternandthatcircadiancontrolis alsosubjecttomodulationbytheenergystatusoftheorganism. Disruptionofeitherthecircadianclockormetabolismcanlead toderangementoftheother,thuspredisposingtometabolic disorderssuchasobesityandtype2diabetes.Futureresearch willcontinuetofocusonexpandingourunderstandingofhow brainandperipheralclockscoordinatelyregulatemetabolicprocessesatboththecell-autonomousandnon-autonomouslevel, hownutrientfluxtranslatesinformationregardingenvironmentalmilieutotheclock,andtheimpactofcircadianrhythms inhumanhealthanddisease. Acknowledgments WethankRaviAllada,Shin-ichiroImai,JosephS.Takahashi,Fred W.Turek,andmembersoftheBasslabforhelpfulcommentsand discussions.K.M.RamseyreceivedsupportfromNIDDKgrant T32DK007169.J.BassissupportedbyNIHgrantsP01AG011412

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