Circadian Regulation Of Lipid Metabolism Proceedings Of .
Proceedings of the Nutrition Society (2016), 75, 440–450 The Author 2016 First published online 26 May 2016doi:10.1017/S0029665116000288The Joint Winter Meeting between the Nutrition Society and the Royal Society of Medicine held at The Royal Society of Medicine,London on 8–9 December 2015Conference on ‘Roles of sleep and circadian rhythms in the origin and nutritionalmanagement of obesity and metabolic disease’Symposium 2: Metabolic and endocrine mechanismsCircadian regulation of lipid metabolismJoshua J Gooley1,2,3Proceedings of the Nutrition Society1Center for Cognitive Neuroscience, Program in Neuroscience and Behavioral Disorders, Duke-NUS Medical School,169857 Singapore2Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 117596 Singapore3School of Psychological Sciences, Monash University, Melbourne, Victoria 3800, AustraliaThe circadian system temporally coordinates daily rhythms in feeding behaviour and energymetabolism. The objective of the present paper is to review the mechanisms that underliecircadian regulation of lipid metabolic pathways. Circadian rhythms in behaviour and physiology are generated by master clock neurons in the suprachiasmatic nucleus (SCN). TheSCN and its efferent targets in the hypothalamus integrate light and feeding signals to entrain behavioural rhythms as well as clock cells located in peripheral tissues, including theliver, adipose tissue and muscle. Circadian rhythms in gene expression are regulated atthe cellular level by a molecular clock comprising a core set of clock genes/proteins. In peripheral tissues, hundreds of genes involved in lipid biosynthesis and fatty acid oxidation arerhythmically activated and repressed by clock proteins, hence providing a direct mechanismfor circadian regulation of lipids. Disruption of clock gene function results in abnormalmetabolic phenotypes and impaired lipid absorption, demonstrating that the circadian system is essential for normal energy metabolism. The composition and timing of meals influence diurnal regulation of metabolic pathways, with food intake during the usual rest phaseassociated with dysregulation of lipid metabolism. Recent studies using metabolomics andlipidomics platforms have shown that hundreds of lipid species are circadian-regulated inhuman plasma, including but not limited to fatty acids, TAG, glycerophospholipids, sterollipids and sphingolipids. In future work, these lipid profiling approaches can be used tounderstand better the interaction between diet, mealtimes and circadian rhythms on lipidmetabolism and risk for obesity and metabolic diseases.Circadian: Metabolism: Lipids: Lipidomics: Metabolomics: ChronobiologyMany behavioural and physiologic processes exhibit a24-h rhythm, including the sleep–wake cycle, feeding patterns and energy metabolism. These rhythms are temporally coordinated by the circadian (‘about a day’) system.Circadian rhythms are generated endogenously andhence the body can keep time even in the absence of periodic environmental stimuli(1). Under natural conditions,the primary synchroniser of the circadian system is thelight–dark cycle, but feeding–fasting cycles can also entrain circadian rhythms(2,3). Over the past 40 years,much has been learned about the structural organisationof the circadian system, including the pathways by whichlight and feeding stimuli are integrated, and efferentpathways that drive daily patterns in behaviour andphysiology. The circadian system ensures that daily patterns of food-seeking behaviour and energy metabolismAbbreviations: BMAL1, brain and muscle aryl hydrocarbon receptor translocator-like protein 1; CLOCK, circadian locomotor output cycles kaput;NPAS2, neuronal PAS domain-containing protein 2; PC, phosphatidylcholine; PGC-1α, PPARγ coactivator 1α; ROR, retinoic acid receptor-relatedorphan receptor; SCN, suprachiasmatic nucleus.Corresponding author: J. J. Gooley, fax 65 6221 8625, email joshua.gooley@duke-nus.edu.sgDownloaded from https://www.cambridge.org/core. IP address: 209.126.7.155, on 27 Apr 2021 at 05:22:45, subject to the Cambridge Core terms of use, available athttps://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665116000288
Proceedings of the Nutrition SocietyCircadian regulation of lipidsare aligned with the solar day length and food availability. This presumably optimises the body’s energyresources and facilitates physiologic adaptation to environmental pressures.In the present paper, we provide a broad overview ofthe role of the circadian system in regulating lipid metabolic pathways. Lipids are integral components of cellular membranes and lipoproteins, and are important forenergy storage and transport. Lipids also function asintracellular and intercellular signalling molecules, withwidespread effects on cellular physiology. A growingbody of research indicates that disruption of circadianclock function leads to dysregulation of lipid metabolism, obesity and metabolic diseases(4). Herein, we reviewhow the circadian system is organised to synchroniselipid metabolic rhythms in peripheral tissues with light–dark and feeding–fasting cycles. We discuss the mechanisms by which the core molecular clock drives rhythms inlipid biosynthesis and catabolism in different metabolictissues, as well as the negative consequences of clockgene dysregulation on energy metabolism. We also review the impact of mealtimes and circadian misalignment on metabolic health, including effects of shiftwork. Finally, we discuss recent studies that have usedmetabolomics and lipidomics platforms to examinecircadian-regulated lipids and effects of the circadianclock and dietary manipulations on lipid metabolism.441human subjects, circadian phase is most commonlydefined by measuring rhythms of core body temperature,melatonin or cortisol (Fig. 1)(14). When measured underconditions that minimise the influence of exogenous(non-circadian) factors, these markers show highamplitude circadian rhythms and can be used to assesscircadian clock output. Exposure to light in the earlypart of the night, when melatonin levels are increasingand core body temperature is decreasing, resets the circadian clock to a later time(1). This is termed a phase delayshift, which is equivalent to shifting circadian rhythms inthe westward direction. In contrast, exposure to light inthe late part of the night or early morning, when melatonin levels are decreasing and core body temperatureis increasing, resets the circadian clock to an earliertime. This corresponds to a phase advance shift, whichis akin to shifting the circadian clock in the eastward direction. Under natural lighting conditions, both phasedelay and advance shifts occur during the course of theday. The circadian system aligns with the light–darkcycle such that, after taking into account the net dailyphase shift, the observed period of the SCN neuralrhythm matches the solar day length. The SCN rhythm,in turn, coordinates behavioural and physiologicrhythms ranging from the sleep–wake cycle to food intake and energy metabolism.Entrainment of feeding circuits and peripheral clocksOrganisation of the circadian systemLight entrainment of behavioural circadian rhythmsCircadian rhythms of behaviour are regulated by a master clock located in the suprachiasmatic nucleus (SCN) inthe anterior hypothalamus. The SCN comprises neuronsthat generate cell-autonomous circadian oscillations ingene expression and neural activity(5). The firing rate ofSCN neurons is highest during the daytime and lowestat night, and closely tracks the circadian rhythm of locomotor activity(6). Because the period of the circadianclock is close to, but not exactly 24 h, the phase ofSCN clock neurons must be reset by a small amounteach day to ensure entrainment to the solar day length.Photic entrainment of circadian rhythms is mediated bya direct retinohypothalamic projection to the SCN thatoriginates from intrinsically photosensitive retinal ganglion cells. The intrinsically photosensitive retinal ganglion cells contain the photopigment melanopsin(7–9),which is most sensitive to short-wavelength blue light,but also receive input from rods and cones(7,10). Hence,both visual photoreceptors and melanopsin cells likelycontribute to photic circadian entrainment of rest–activity and feeding cycles.Upon activation by light, intrinsically photosensitiveretinal ganglion cells release glutamate and pituitary adenylate cyclase-activating polypeptide onto SCN neurons(11,12). This triggers Ca2 influx and activatesintracellular signalling cascades leading to phase resetting of the core molecular clock mechanism(13). The magnitude and direction of resetting depends on the circadianphase (i.e. internal body time) of the light stimulus. InThe master circadian pacemaker in the SCN synchronises clocks in other parts of the brain and in peripheraltissues(15,16). Entrainment of peripheral clocks can potentially occur through neural and endocrine pathways, orindirectly through effects of the SCN rhythm on rest–activity and feeding cycles (Fig. 2). The SCN sends itsdensest projections to other hypothalamic nuclei, including the subparaventricular zone and dorsomedial hypothalamic nucleus, which are also required for normalcircadian expression of behavioural rhythms, includingfeeding(17–19). In addition to receiving input from appetite circuits, the dorsomedial hypothalamic nucleus contains different populations of neurons that project tothe sleep-promoting ventrolateral preoptic nucleus andthe wake-promoting lateral hypothalamic area(17). Theprojection to the lateral hypothalamic area contacts neurons containing the neuropeptide orexin, which increasesfood-seeking behaviour and plays a key role in stabilisingsleep–wake behaviour. The circadian pattern of sleep–wake is therefore tightly coupled with feeding and energymetabolism, with integration of these pathways occurring at the level of the hypothalamus.The SCN regulates circadian rhythms of melatoninand cortisol through its projections, either directly or indirectly, to the paraventricular hypothalamic nucleus.While the phase-resetting effects of melatonin on SCNneural activity are well-established, growing evidencesuggests that melatonin might also influence the phaseof circadian rhythms in peripheral tissues, includingadipocytes(20). Through its effects on the hypothalamic–pituitary–adrenal axis, the SCN regulates circadian secretion of glucocorticoids, which have been implicatedDownloaded from https://www.cambridge.org/core. IP address: 209.126.7.155, on 27 Apr 2021 at 05:22:45, subject to the Cambridge Core terms of use, available athttps://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665116000288
442J. J. GooleyMolecular generation of circadian rhythms in lipidsProceedings of the Nutrition SocietyRegulation of clock-controlled genes involved in lipidmetabolismFig. 1. Circadian regulation of physiologic measures in a humansubject. Circadian rhythms of salivary melatonin, salivary cortisoland core body temperature are shown for a representativeindividual who was studied under constant environmentalconditions over a 24-h period. Data were collected as part of alaboratory study that was designed to evaluate the timing ofcircadian rhythms in research volunteers(14). The grey bar indicatesthe subject’s usual sleep period.in resetting of peripheral clocks(21). The syntheticglucocorticoid dexamethasone can shift the phase of circadian gene expression in peripheral tissues(22), and therate of entrainment of peripheral clocks is modulated byglucocorticoid signalling(23). Whereas light is the primarysynchroniser of SCN neural activity and melatonin secretion, diurnal cycles of feeding and fasting can entrain circadian gene expression patterns in peripheral tissues(24).Normally, circadian rhythms of sleep–wake and food intake are synchronised, but peripheral clocks can entrainto time-restricted feeding schedules, even when theSCN clock is rendered dysfunctional(25). Recently, ithas been established that the molecular circadian clockin peripheral tissues is sensitive to nutrient sensing pathways, suggesting that the content and timing of meals caninfluence the phase of peripheral clocks(26–28). Hence, thecircadian system is hierarchically organised to integratelight and feeding signals, but peripheral clocks are especially sensitive to periodic feeding stimuli.To understand how the circadian system exerts its influence on lipid pathways, it is first important to reviewthe molecular mechanisms that generate circadian oscillations in gene expression (Fig. 3). In SCN neurons andin cells in peripheral tissues, circadian rhythms are generated by transcriptional–translational feedback loops involving a core set of clock genes and proteins(5).During the daytime, the transcription factor brain andmuscle aryl hydrocarbon receptor translocator-like protein 1 (BMAL1) forms a heterodimer with either circadian locomotor output cycles kaput (CLOCK) or withneuronal PAS domain-containing protein 2 (NPAS2).CLOCK is thought to be the primary binding partnerfor BMAL1 in peripheral tissues, whereas bothCLOCK and NPAS2 are involved in the molecularclock mechanism in SCN neurons and other forebrainareas. The BMAL1:CLOCK/NPAS2 transcriptionalcomplex activates expression of Period (Per1 and Per2)and Cryptochrome (Cry1 and Cry2) genes by bindingto E-box sequences in the promoter region(29–31). ThePER and CRY proteins accumulate in the cytoplasm,and then translocate to the nucleus in the evening to repress their own transcription by interacting with theBMAL1:CLOCK/NPAS2 complex(32–35). Hence, PERand CRY levels are higher during the day and lower atnight, similar to the SCN neural activity rhythm. The circadian time course of gene expression is regulated bypost-translational mechanisms, including phosphorylation-dependent ubiquitination and proteosomal degradation of PER and CRY proteins in the cytoplasm(36–40),allowing for a new cycle of transcription by relieving inhibition of the BMAL1:CLOCK/NPAS2 transcriptionalcomplex.As part of another molecular feedback loop, BMAL1:CLOCK/NPAS2 activates transcription of the nuclearreceptors Rev-erbα and Rev-erbβ, whose protein productsrepress Bmal1 and Npas2 expression by binding to retinoicacid receptor-related orphan receptor (ROR) response elements in the promotor region(41,42). This is achieved inpart by REV-ERBα-dependent recruitment of the nuclearreceptor corepressor/histone deacetylase 3 complex.Additionally, ROR genes (RORα, RORβ and RORγ) arerhythmically expressed and their protein products activateBmal1 and Npas2 transcription by binding to ROR response elements, thus competing with and having the opposite effect of REV-ERB proteins(43–45). REV-ERBαmight also act as a transcriptional repressor for Clockby binding to a REV-ERB response element, althoughROR proteins do not appear to regulate Clock gene expression(46). The aforementioned feedback loops constitutepart of the core molecular mechanism for circadian geneexpression; however, there are other pathways by whichcircadian timing can be regulated at the cellular level, asreviewed in detail elsewhere(47,48).Notably, the transcriptional activators and repressorsthat are part of the molecular circadian clock interactnot only with other clock genes and proteins, but alsoDownloaded from https://www.cambridge.org/core. IP address: 209.126.7.155, on 27 Apr 2021 at 05:22:45, subject to the Cambridge Core terms of use, available athttps://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665116000288
Circadian regulation of lipids443Fig. 2. Organisation of the circadian system. Exposure to the light–dark cycle synchronises the mastercircadian clock in the suprachiasmatic nucleus (SCN) in the hypothalamus. The SCN clock cansynchronise peripheral clocks through its effects on behavioural rhythms (e.g. rest–activity and feeding–fasting cycles), as well as neural and endocrine pathways. 3v, third ventricle; fx, fornix; oc, optic chiasm.Proceedings of the Nutrition Societywith thousands of other gene targets, termed clockcontrolled genes. These clock-controlled genes includegenes involved in energy metabolism, as well as othertranscription factors, hence allowing the circadian clockto regulate diverse cellular processes. This has beendemonstrated in several studies examining genome-widebinding targets (i.e. the cistrome) of clock proteins acrossthe circadian cycle. For example, thousands of DNAbinding sites in mouse liver are rhythmically occupiedby BMAL1, including genes involved in sterol andTAG metabolic pathways(49,50). Similarly, the circadiancistromes for REV-ERBα, nuclear receptor corepressorand histone deacetylase 3 overlap extensively and areenriched for genes involved in lipid metabolism(51–53).Circadian rhythms in genome-wide occupancy forBMAL1, REV-ERBα and REV-ERBβ show strongoverlap for metabolic pathways and transcriptionalregulators in the liver(52), and similar findings havebeen reported for other core clock proteins (BMAL1,CLOCK, NPAS2, PER1, PER2, CRY1 and CRY2)(54).Importantly, the circadian clock can exert its widespreadinfluence on energy metabolism by regulating ratelimiting steps in metabolic pathways(55), as well asnuclear receptors, including REV-ERB and ROR proteins, and PPARα, PPARγ and PPARδ, which are keytranscriptional regulators of lipid metabolism. These nuclear receptors are diurnally regulated in liver, white andbrown adipose tissue, and muscle(56), hence coupling themolecular clock with transcriptional networks involvedin energy metabolism(57).Fig. 3. Molecular circadian clock mechanism for regulating lipidmetabolism. Brain and muscle aryl hydrocarbon receptortranslocator-like protein 1 and circadian locomotor output cycleskaput (BMAL1:CLOCK) heterodimers bind to E-box elements in thepromoter region and drive transcription of Per and Cry genes, whoseprotein products dimerise and inhibit their own transcription byinteracting with the BMAL1:CLOCK transcriptional complex. TheBMAL1:CLOCK heterodimer also activates transcription of Rev-erband Ror genes. Retinoic acid receptor-related orphan receptor (ROR)and REV-ERB proteins competitively bind to ROR response element(RORE) sequences in the Bmal1 promoter region, thus activating orrepressing gene expression, respectively. The molecular clockproteins also regulate circadian gene expression of hundreds ofclock-controlled genes (ccgs) that are involved in lipid metabolism.Circadian regulation of lipids in metabolic tissuesLipid pathways are under circadian control in all of themajor metabolic organs. Here, we shall highlight just afew of the mechanisms by which the circadian systemregulates lipid metabolism. In the liver, all members ofthe PPAR family are diurnally regulated(56), includingPPARα which promotes mitochondrial fatty acidβ-oxidation through its interaction with the transcriptional coactivator PPARγ coactivator 1α (PGC-1α).PPARα and PGC-1α cycle together and promote utilisation of fatty acids at the beginning of the night in mice,coincident with the onset of foraging(58). PGC-1α alsoDownloaded from https://www.cambridge.org/core. IP address: 209.126.7.155, on 27 Apr 2021 at 05:22:45, subject to the Cambridge Core terms of use, available athttps://www.cambridge.org/core/terms. https://doi.org/10.1017/S0029665116000288
Proceedings of the Nutrition Society444J. J. Gooleyregulates clock gene expression through its interactionwith ROR family members, and is required for cellautonomous clock function in the liver(59). Hence,PGC-1α plays a key role in coordinating circadianclock function and energy metabolism. Diurnal variationin fatty acid synthesis is mediated in part by the effects ofthe circadian clock on sterol regulatory element-bindingprotein-1c and its downstream targets(60,61). The molecular circadian clock is also required for circadian expression of rate-limiting enzymes for cholesterol and bileacid synthesis, namely 3
intracellular signalling cascades leading to phase reset-ting of the core molecular clock mechanism(13). The mag-nitude and direction of resetting depends on the circadian phase (i.e. internal body time) of the light stimulus. In human subjects, circadian phase is most commo
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