Circadian Clocks Make Metabolism Run

Review

Circadian Clocks Make Metabolism Run

Flore Sinturel 1, 2, 3, 4 , Volodymyr Petrenko 1, 2, 3, 4 and Charna Dibner 1, 2, 3, 4 1 - Department of Medicine, Division of Endocrinology, Diabetes, Hypertension and Nutrition, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, Geneva, 14, Switzerland 2 - Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland 3 - Diabetes Center, Faculty of Medicine, University of Geneva, Geneva, Switzerland 4 - Institute of Genetics and Genomics of Geneva (iGE3), University of Geneva, Geneva, Switzerland

Correspondence to Charna Dibner, Flore Sinturel: Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Rue Michel-Servet, 1, CH-1211, Geneva, 14, Switzerland. [email protected], [email protected] https://doi.org/10.1016/j.jmb.2020.01.018 Edited by Achim Kramer

Abstract Most organisms adapt to the 24-h cycle of the Earth's rotation by anticipating the time of the day through lightdark cycles. The internal time-keeping system of the circadian clocks has been developed to ensure this anticipation. The circadian system governs the rhythmicity of nearly all physiological and behavioral processes in mammals. In this review, we summarize current knowledge stemming from rodent and human studies on the tight interconnection between the circadian system and metabolism in the body. In particular, we highlight recent advances emphasizing the roles of the peripheral clocks located in the metabolic organs in regulating glucose, lipid, and protein homeostasis at the organismal and cellular levels. Experimental disruption of circadian system in rodents is associated with various metabolic disturbance phenotypes. Similarly, perturbation of the clockwork in humans is linked to the development of metabolic diseases. We discuss recent studies that reveal roles of the circadian system in the temporal coordination of metabolism under physiological conditions and in the development of human pathologies. © 2020 Elsevier Ltd. All rights reserved.

Organization of the Mammalian Circadian Clock System During the course of evolution, light-sensitive organisms have developed an internal timing system that provides the ability not only to follow the environmental changes related to the Earth's rotation but also to anticipate these changes. This anticipatory mechanism, which is dubbed the circadian clock, coordinates the rhythmic regulation of the vast majority of physiological and behavioral processes in mammals, including food intake, nutrient processing, xenobiotic detoxification, and many others, with a periodicity of “about a day” (in Latin “circa”, around; “diem”, day). Indeed, physiological processes are temporally coordinated by the circa-

0022-2836/© 2020 Elsevier Ltd. All rights reserved.

dian system at all levels, from the entire organism to individual cells. This coordination is ensured by the hierarchical organization of the complex network of oscillators. The circadian system comprises a master pacemaker encompassing approximately 20,000 neurons in rodents and 100,000 neurons in humans that is located in the suprachiasmatic nucleus (SCN) of the hypothalamus [1e3], and cell-autonomous circadian oscillators present in nearly every cell of the body (Fig. 1; [4,5]). The light-dark cycle synchronizes the SCN on a daily basis, which in turn sets the phase of slave oscillators operating in peripheral organs via a wide variety of signaling cues, including neuronal and hormonal pathways (Fig. 1 [6e8]). At the cellular level, the molecular mechanism responsible for driving circadian oscillations is based on a

Journal of Molecular Biology (2020) 432, 3680e3699

Circadian Regulation of Metabolism

transcription-translation feedback loop regulating core clock gene expression, with a similar molecular composition observed in SCN neurons and in the peripheral organs [7e11]. The two central components of the molecular clock are the transcription factors CLOCK (Circadian Locomotor Output Cycles Kaput) and BMAL1 (Brain and Muscle ARNT-Like 1) that form a heterodimeric complex driving the rhythmic expression of numerous clock-controlled genes outside the core clock machinery. The CLOCK-BMAL1 dimer activates the transcription of the Period (Per) and Cryptochrome (Cry) genes, which encode the repressor proteins PER1, PER2, PER3, CRY1, and CRY2 [12]. When present at sufficient concentrations, the PER and CRY complex inhibits CLOCK-BMAL1 activity [13,14]. Consequently, the transcription of Per and Cry is no longer stimulated by the CLOCK-BMAL1 activators, resulting in decreased levels of the PER and CRY proteins. Once PER and CRY levels decrease to a critically low threshold at which they stop inhibiting their synthesis, a new cycle of PER and CRY protein accumulation begins, thus generating oscillatory changes in the levels of the core clock transcripts and proteins that persist for approximately 24 h [9]. Protein-protein interactions among the core clock components represent an additional regulatory level of this autoregulatory loop [15], as the interaction between CRY1 and PER2 proteins is modulated by the binding of zinc and disulphide bond formation [13]. In a secondary feedback loop, the CLOCKBMAL1 complex controls the rhythmic expression of the genes encoding the REV-ERB nuclear hormone receptors (REV-ERBa and REV-ERBb) and RORa (and RORb in neurons) [16]. In turn, REV-ERBa and RORa compete for the same RORE elements within the Clock and Bmal1 promoter regions, resulting in the repression or activation of Clock and Bmal1 transcription, respectively. The recently identified protein CHRONO binds the promoter region of Bmal1 in a circadian manner and thereby inhibits its function [17,18]. Mathematical modeling suggests that the feedback loops may differ between tissues, further contributing to the hierarchy of clocks in mammalian tissues, and these differences potentially account for the organ-specific variations in the circadian landscape [19]. Beyond the transcription-translation negative feedback loop, post-translational modifications of the core clock proteins provide an additional level of regulation of the molecular oscillator [20e24]. Some of these modifications, which reflect the energetic status of the cells, represent a tight link between metabolism and the circadian clock [25] that will be further discussed in Chapter 2. Phosphorylation is one of the key post-translational modifications, which is involved in regulating the core clock loop, as well as the downstream clock-regulated targets

3681 [26]. The application of advanced phosphoproteomic analyses to the circadian studies [27] enabled researchers to further determine the importance of rhythmic protein phosphorylation. For instance, protein phosphorylation driven by sleep-wake cycles in the mouse brain was reported to control synaptic function [28,29]. Importantly, phosphoproteomic studies revealed rhythmically regulated phosphorylation sites within several core clock components, such as CLOCK and BMAL1 [27,30e32]. BMAL1 phosphorylation is regulated by the insulin-AKTmTOR pathway that is activated in the postprandial state [27,33,34]. In addition, high levels of glucose directly modulate the molecular oscillators via OGlcNAcylation of the core clock proteins [35,36]. Glucose is converted to uridine diphosphate Nacetylglucosamine (UDP-GlcNAc) via the hexosamine pathway, and this product is the substrate of the O-b-D-N-acetylglucosamine (O-GlcNAc) [37]. In turn, O-GlcNAc transferase catalyzes the reversible O-GlcNAcylation of the CLOCK, BMAL1, and PER2 proteins to modulate the length of the circadian period [35,36,38]. In addition, acetylation of the clock proteins directly affects their stability and activity. Cellular acetyl-CoA pools represent the substrates for the acetylation of histones, resulting in the regulation of Per and Cry transcription [39] and the translation of the core clock proteins BMAL1 and PER2 [40e42]. Acetylation of BMAL1 by the lysine acetyltransferase TIP60 recruits the BRD4-P-TEFb complex and results in the elongation of circadian transcripts [43]. Further post-translational modifications that participate in fine-tuning the molecular clock and clock-controlled proteins comprise ubiquitination, SUMOylation, or methylation [20]. Nuclear to cytoplasmic translocation of the core clock proteins represents additional level of regulation of the molecular loop. For instance, the nuclear import protein Transportin 1 was recently suggested to modulate the core clock oscillators through its effect on the intracellular localization of PER1 [44]. Similarly, phosphorylation of PER2 by casein kinase 2 (CK2) is required to sustain its stability and proper nuclear accumulation [45].

Orchestrating the Web of Clocks in the Body The circadian system encompasses a myriad of individual cell-autonomous oscillators [4] that must be synchronized on a daily basis to coordinate physiological processes at the organismal level. Feeding-fasting cycles, the levels of feeding-related hormones and metabolites, and rhythmic changes in body temperature and oxygen levels represent major signaling cues driving the activation of peripheral oscillators.

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Fig. 1. Temporal regulation of the body metabolism by the web of circadian oscillators. The circadian system comprises a central clock that is located in the SCN and peripheral clocks located in the organs. Peripheral oscillators operating in metabolic organs, such as the liver, muscle, white adipose tissue, pancreas and gut, function in concert with the central clock to orchestrate glucose, lipid and protein metabolism. These coordinated actions have also been observed at the cellular level, where intracellular metabolism is regulated by cell-autonomous clocks that are present in most cells of the body. In the liver, gluconeogenesis, glycogen storage, and O-GlcNAcylation of proteins are regulated by the hepatocyte oscillators that are orchestrating the changes in key enzymes catalyzing these processes. Protein synthesis displays circadian rhythmicity at multiple steps, resulting in rhythmic changes in the levels of a large number of hepatic proteins. In the endocrine pancreas, the processes underlying insulin and glucagon secretion exhibit circadian rhythmicity. In addition, glucose homeostasis is controlled by the rhythmic secretion of incretin hormones from the gut. In the skeletal muscle, local

Circadian Regulation of Metabolism

Feeding Although light represents the predominant Zeitgeber (“time-giver” from German, i.e., synchronization cue) for the central pacemaker clock, feeding-fasting cycles are essential timing cues for the peripheral oscillators. Under physiological conditions, food consumption coincides with the activity phase to a large extent, approximately 75e80% in mice [46]. Feeding is a particularly potent synchronizer of the metabolically active organs [47], as a restriction of the availability of food to the daylight hours for nocturnal rodents (inversed feeding regimen) proved sufficient to uncouple the clocks operating in the liver from the clocks operating in the SCN [48,49]. In addition to the timing of feeding, the composition of the consumed food exerts an important effect on the central and peripheral clockwork. For instance, mice fed a high-fat diet ad libitum display a perturbed eating pattern and locomotor activity, concomitant with flattened oscillations of the core clock genes [50e52]. Furthermore, high-fat, high-sugar, and protein-only diets led to alterations in the oscillatory characteristics of the core clock genes in the rodent liver [53,54]. Feeding-related hormones and metabolites The hormones related to the feeding-fasting rhythms modulate the circadian system at several levels [55]. The hepatokine FGF21, which is mainly secreted by the liver in response to fasting, modulates locomotor activity and insulin and corticosterone levels through the interaction between the FGF21 receptors and bKlotho in SCN neurons [56,57]. In turn, FGF21 levels are controlled by the clock via REV-ERBa [58], resulting in its oscillatory pattern in mouse and human blood, particularly in the period of prolonged fasting [59]. Ketone bodies produced by the liver in response to prolonged fasting also affect the master clock to induce food anticipation behavior [60]. The orexigenic hormone ghrelin is secreted by the stomach upon fasting [61], and it exhibits a circadian oscillatory profile in mouse serum [62]. Ghrelin was shown to set the phase of the mouse SCN in vitro [63] and is involved in maintaining sexual dimorphism [64]. In humans, ghrelin exhibits a circadian rhythmic pattern in plasma that is particularly pronounced during a 24h fasting period [65], and it exerts a beneficial effect on sleep [66]. As Bmal1 was not required for proper

3683 ghrelin secretion by the ghrelinoma cells in vitro [67], further studies are needed to determine whether the circadian clock directly regulates ghrelin secretion. In addition, food intake directly resets liver clocks by stimulating oxyntomodulin secretion from the gut [68]. During feeding, anabolic processes are triggered by the activation of the insulin-pAKT-mTOR pathway, whereas during fasting, AMP-activated protein kinase activation triggers catabolic processes and inhibits mTOR activity [69]. AMP-activated protein kinase is a sensor of cellular energy levels that modulates the core clock machinery by phosphorylating CRY and PER [70,71]. In addition, the fooddriven regulation of peripheral clocks involves the nutrient-sensitive transcription factors TFEB and TFE3 that couple intracellular metabolism with autophagy and with molecular clocks by regulating Rev-erba expression [72]. The molecular clocks are also sensitive to the ratio of reduced to oxidized nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD) molecules, which are additional sensors of cellular energy status. Both NAD and FAD serve as cofactors that regulate the functions of the core clock proteins. Indeed, the oxidized form of NAD, NAD þ, prevents the deacetylation of clock components by Sirtuin 1 (SIRT1, SIRT-family protein) and the poly-ADP-ribosylation mediated by poly(ADP-ribose) polymerase 1 (PARP1) [40e42,73]. These two modifications affect the transcriptional activity of the CLOCK-BMAL1 complex [74]. For instance, NAD þ is used by PARP1 to add poly(ADP)ribose residues to CLOCK, subsequently decreasing CLOCK-BMAL1 binding to DNA and delaying repression mediated by the CRY-PER complex [73]. In turn, CLOCK-BMAL1 regulates the expression of the nicotinamide phosphoribosyltransferase (Nampt) gene encoding the rate-limiting enzyme of the NAD þ salvage pathway. This pathway leads to intracellular rhythmic variations in NAD þ levels [75,76]. Furthermore, FAD levels are rhythmically regulated in the nucleus, and they control CRY protein degradation by competing with the ubiquitin ligase FBXL3 [77]. Strikingly, carbon monoxide (CO) levels represent an important link between the core clock machinery and metabolism. Indeed, the rhythmic formation of CO in the process of haem degradation maintains circadian and metabolic cycles through the CO-dependent suppression of circadian transcription by attenuating the binding of the CLOCK-BMAL1 complex to its targets.

oscillators control the expression of genes and proteins involved in the insulin signaling pathway, cytokine secretion, and lipid metabolism. Key hormones involved in the feeling of satiety, such as leptin and ghrelin, are rhythmically secreted by the adipocyte tissue and the stomach, respectively. Diurnal variations in lipid metabolism have been observed in hepatocytes, adipocytes, and skeletal muscle cells. Indeed, the circadian clock regulates the expression of key enzymes involved in lipolysis and the synthesis of free fatty acids (FFAs). Subsequently, most of these metabolites respond to central and peripheral clocks by modulating the rhythms of the body.

3684 Accordingly, the suppression of CO rhythmicity perturbs hepatic clocks and hepatic glucose metabolism [78]. Finally, the production of acetyl-CoA in mitochondria is regulated by the circadian system through the rhythmic deacetylation of acetyl-CoA synthetase (AceCS1) that catalyzes the synthesis of acetyl-CoA by SIRT1 [79]. Body temperature Body temperature rhythms represent an additional potent systemic Zeitgeber for the peripheral oscillators [80e82]. Although the amplitude of morning-evening fluctuations in mammalian body temperature displays a narrow range of 1  Ce4  C, simulated temperature cycles with a step of only 3  C (35.5  Ce38.5  C) were sufficient to synchronize the circadian clocks operating in cultured fibroblast cells in vitro [80]. This synchronization is likely driven by temperature sensor proteins comprising cold-inducible RNA-binding protein 1 (CIRPB) and heat-shock factor 1 (HSF1) that regulate the molecular clock. CIRBP expression is activated by cold temperatures. Once activated, it modulates Clock pre-mRNA maturation [80,83]. Upon an increase in body temperature, Hsf1 expression is induced, and the protein subsequently induces Per2 expression [84,85]. This connection is reciprocal because body temperature variations are subject to direct regulation by the circadian clock, with REV-ERBa driving rhythmic expression of the Ucp1 gene in the brown adipose tissue and thus contributing to daily oscillations in the body temperature [86]. Oxygen levels and exercise Daily nutrient absorption is closely linked to rhythmic oxygen consumption and subsequent blood and tissue oxygenation [87]. Indeed, the oxygen supply appears to be a potent synchronizing signal for peripheral oscillators in mice [88e90]. The molecular mediator between the oxygen levels and the core clock components is hypoxia-inducible factor 1a (HIF1a) [88,89], which is activated in the skeletal muscle during physical exercise. Notably, the response to acute hypoxia varies across the day, and it is tissue dependent [91]. Recently, the key myogenic regulatory factor MYOD1 was shown to be required for the proper Bmal1 circadian amplitude and function in the skeletal muscle [92]. Mouse physical performance, as determined by the duration of running on treadmills and blood glucose level measurements, shows daytime variations between the beginning and end of the active phase [93]. This daily variation in the exercise capacity is abolished in Per1/Per2 KO mice [93]. However, the global exercise endurance capacity is

Circadian Regulation of Metabolism

not altered in mice with a muscle-specific loss of Bmal1 [94]. Consistent with these observations in mice, the amount of oxygen consumed during exercise is lower in the afternoon than in the morning in humans, suggesting a better exercise efficiency at the end of the day [93]. In turn, physical activity drives distinct metabolic responses in the mouse skeletal muscle according to the time of the day [93,95,96]. Furthermore, lactate is one of the most important metabolites whose levels are increased in the circulation during physical exercise and during fasting [88,97]. Lactate has been proposed to directly modulate the molecular clock through the HIF1a-mediated acidification of the medium [98] and by modifying NPAS2-BMAL1 transcriptional activity [74], possibly by modulating the NAD þ/NADH ratio [97].

Peripheral Clocks Coordinate Metabolism in the Body The interaction between circadian and metabolic cycles is reciprocal [9,99e101]. Importantly, the circadian system ensures a temporal partitioning of catabolic and anabolic reactions that are governed by the clocks at several levels, as will be discussed in this chapter, thus synchronizing the metabolism of the body to the feeding-fasting cycle. Hunger levels are rhythmically controlled by the circadian system within the AgRP neurons [102]. Glucose homeostasis is tightly regulated by the coordinated activity of the oscillators operating in the metabolic organs (Fig. 1 [103,104]). Indeed, during the activity/feeding phase, the skeletal muscle, adipose, and liver cells take up glucose, while glucose is excreted from the liver during the resting phase [105]. The rhythmic secretion of insulin and glucagon from the pancreas and the incretin hormone GLP1 from the gut completes the fine-tuning of the blood glucose homeostasis throughout the day (Fig. 1 [106e111]). Similarly, lipid and protein metabolism are controlled by the circadian oscillators at several levels. In this chapter, we will discuss recent advances in the regulation of glucose, lipid, and protein homeostasis by the peripheral oscillators operating in metabolic organs, as summarized in Fig. 1. In the liver Circadian oscillators coordinate the metabolic function of the liver at multiple levels [104,112]. The liver plays an essential role as a buffer for glucose variations arising from rhythmic food consumption. The peak of the rhythmic expression of glucose transporters and glucagon receptor at the beginning of the active phase enables efficient

Circadian Regulation of Metabolism

glucose uptake by the hepatocytes [113,114]. Concordantly, liver-specific Bmal1 KO mice exhibit hypoglycemia during the fasting period due to increased glucose clearance [105]. Once glucose enters hepatocytes, it will be used for energy production via glycolysis or stored as glycogen, depending on the energy status (Fig. 1). Glycogenesis is promoted by the rhythmic activity of glycogen phosphorylase [115], the liver-specific glycogen synthase kinase 3 (GSK3) [116], and glycogen synthase 2 (GYS2) through its direct transcriptional activation by CLOCK [117]. Notably, GSK3 also regulates the activity of the O-GlcNAc transferase [35] responsible for the rhythmic O-GlcNAcylation of proteins (discussed previously in Chapter 1 in the context of the regulation of core clock components). In the fasted state, CRY proteins play a central role in promoting gluconeogenesis. Liver-specific depletion of Cry1 and Cry2 has been shown to stimulate de novo glucose production in hepatocytes, thus increasing the blood glucose concentration [118]. On the one hand, CRY proteins regulate glucose synthesis by inhibiting glucocorticoid receptors [119,120]. On the other hand, they mediate glucagon signaling by sequentially inhibiting cAMP accumulation, CREB activity, and the expression of phosphoenolpyruvate carboxykinase 1 (PCK1), the key enzyme in gluconeogenesis [118,121]. This CRYdependent regulation of gluconeogenesis is mediated by the rhythmic degradation of CRY1 through autophagy [122]. Large-scale lipidomics studies of the mouse liver revealed that a significant proportion of the lipid species oscillate over 24 h through processes modulated by both rhythmic feeding and the intrinsic liver clock because the temporal lipidomics profile is drastically altered in the Per1/Per2 double KO mice and upon the inversion of the feeding cycle [123]. Strikingly, a higher percentage of lipid metabolites exhibited rhythmic profiles when assessed separately in liver nuclei and mitochondria [124]. Consistent with these findings, the levels of key enzymes catalyzing lipid biosynthesis, L-carnitine palmitoyltransferase 1 and 2 that mediate fatty acyl group transfer to the mitochondrion, and the ATP citrate lyase enzyme that controls acetyl-CoA export from the mitochondria to the cytoplasm display daily variations that are mainly driven by rhythmic feeding [30,121,123]. Moreover, the key metabolic regulator PGC-1a interacts with ROR proteins in the liver and the skeletal muscle, representing the mechanistic link between the circadian clock machinery and lipid and glucose metabolism [125]. The nuclear receptor REV-ERBa regulates lipid metabolism in the liver because Rev-erba KO mice develop fatty liver disease [126,127]. Indeed, REV-ERBa controls the circadian expression of numerous genes involved in fatty acid synthesis, such as elongation of very long chain fatty acids (Elovl) and acyl-CoA synthetase

3685 short-chain family member 3 (Acss3) [128]. Together with HDAC3, REV-ERBa regulates glycerol and triglyceride metabolism by modulating the expression of key enzymes in the glycerol-3-phosphate pathway [126]. Moreover, REV-ERBa is required for the circadian activity of enzymes and transcription factors involved in cholesterol metabolism and bile acid homeostasis, namely sterol regulatory elementbinding transcription factor (SREBP) [129]. Recent advances in developing approaches for large-scale protein screens facilitated a surprising discovery that only a limited portion of the rhythmically expressed transcripts are translated in a rhythmic manner, and similarly, not all the rhythmic proteins are encoded by the rhythmic transcripts [23,32,130]. In vivo SILAC experiments revealed circadian oscillations of 6% of the total liver proteome that were mainly driven by rhythmic feeding [23,130,131]. A large fraction of these rhythmic proteins comprises secreted proteins that consistently exhibit oscillations in the bloodstream [32,130]. Global mRNA translation is more active during the feeding/activity/dark phase of nocturnal animals than in the fasting/light/rest phase [132e134]. This rhythmic mRNA translation may partially explain the discrepancy between the temporal profiles of proteins and related mRNAs observed in the liver [23,130]. The mTOR-S6 kinase pathway activates general protein translation by regulating the expression of mRNAs involved in ribosome biogenesis [135]. Strikingly, clock- and feeding-dependent regulation of rRNA maturation and ribosome assembly results in significant changes in hepatocyte size and oscillations of the whole molecular content of the liver (RNA and proteins), with a peak at the end of the active phase [134,136]. Ribosome profiling experiments also revealed the preferential translation of specific subsets of mRNAs involved in ribosome biogenesis and mitochondrial proteins driven by feeding rhythms [137,138]. Altogether, these mechanisms of general rhythmic protein synthesis are particularly important for the metabolic function of the liver because they contribute to the oscillatory expression of the key regulators of nutrient processing and detoxification. Post-translational modifications represent an additional layer of regulation of the circadian rhythmic proteome. For instance, REVERBa itself, in complex with O-GlcNAc transferase, modulates the rhythmic O-GlcNAcylation of many proteins, some of which are involved in glucose and lipid metabolism in the liver [139]. Global rhythmic protein acetylation mediated by the circadian activity of sirtuins is involved in regulating lipid metabolism in peripheral tissues [126,140]. A circadian analysis of the mouse liver acetylome identified a high level of enrichment of rhythmic acetylation sites in mitochondrial proteins [31,141]. This process is regulated by both the circadian clock and rhythmic feeding [31],

3686 suggesting the circadian control of mitochondrial activity [142]. Notably, given the essential role of rhythmic feeding in regulating hepatic metabolism [49], most of the studies discussed here highlight the effects of both intrinsic liver clocks and rhythmic feeding on the metabolic function of the liver, without making a clear distinction between the two [143]. In the endocrine pancreas The endocrine pancreas plays a pivotal role in the humoral regulation of glucose homeostasis by secreting two counter-regulatory hormones, insulin and glucagon, which decrease or increase the blood glucose levels, respectively. Functional circadian clocks were characterized in intact rodent and human pancreatic islets [107,144]. Interestingly, molecular oscillators operating in separate a- and b-cells exhibited distinct circadian characteristics when synchronized in culture with physiologically relevant molecules such as somatostatin analogues, GLP1 receptor agonists, glucagon, and adrenaline [108,145]. A functional molecular clock in human and rodent pancreatic islets is essential for proper insulin secretion because the perturbation of the islet clock in either genetic mouse Bmal1 KO models or siCLOCK-mediated perturbation in human islets resulted in reduced insulin release and a diabeteslike phenotype [106,107,146e149]. Moreover, bcell-specific Bmal1 KO attenuates the metabolic adaptation to high-fat dieteinduced obesity in mice [150]. Large-scale transcriptome analyses conducted in mouse and human pancreatic islets over 24 h indicated that the circadian clock controls the expression of genes involved in the transport and secretion of insulin, but not in insulin synthesis [106,108,144,148,151]. In the skeletal muscle Skeletal muscle is responsible for 70e80% of insulin-stimulated glucose uptake in the postprandial state, therefore representing the largest insulinsensitive organ in the body [152]. A functional circadian clock in the skeletal muscle has been characterized in rodents [153,154] and humans [155]. The muscle clock is synchronized by the SCN, food intake, and physical exercise [156e159]. Insulin sensitivity and mitochondrial respiration in the skeletal muscle display circadian variations in mice [160e162] and humans [142,163]. Indeed, the levels and localization of the glucose transporter GLUT4, which plays a critical role in regulating blood glucose homeostasis, are controlled by the CLOCK-BMAL1 complex [160]. Furthermore, a large number of the genes that are rhythmically expressed in the mouse and human skeletal muscle are involved in regulating lipid metabolism [164,165]. Recently, Dyar and

Circadian Regulation of Metabolism

colleagues identified the key direct target genes of BMAL1 and REV-ERBa in the skeletal muscle using ChIP-sequencing. Furthermore, they conducted thorough transcriptomic, metabolic, and lipidomic analyses of muscle-specific Bmal1 KO mice and observed significant perturbations in fatty acid, triglyceride, and phospholipid metabolism in this context [94]. The absence of Bmal1 in the skeletal muscle led to reduced levels of triglycerides, owing to (i) the downregulated expression of the Dgat2 gene, an enzyme responsible for the conversion of diacylglycerols to triglycerides in the mouse muscle and (ii) the upregulation of REV-ERBa target genes involved in lipid metabolism [94]. Circadian regulation of enzymatic activity has been recently reported in the skeletal muscle, further highlighting an essential role for the circadian system in the temporal separation of metabolic processes. For instance, peak activities favoring branching points or linear metabolic pathways are temporally separated, optimizing a rhythmic pathway flux [166]. In human skeletal muscle cells, circadian clocks orchestrate gene transcription, the secretion of the key myokines (including IL6 and MCP1), glucose uptake, and lipid homeostasis in healthy human volunteers [155,165,167,168]. The observed circadian regulation is derived from the skeletal muscle cell-autonomous clocks because abolishing cellular oscillators with an RNAi approach strongly attenuated glucose uptake and myokine secretion and perturbed oscillations in the levels of transcripts and lipid metabolites [155,165,167]. Notably, the expression of large portion of genes encoding the key regulators of insulin signaling and glucose uptake was perturbed following siCLOCK-mediated clock perturbation, concomitant with significantly diminished basal and insulin-induced glucose uptake [165]. Regarding lipid homeostasis in the human skeletal muscle, temporal profiles of greater than 20% of lipid metabolites exhibited circadian oscillations in human serial muscle biopsies collected for 24 h in vivo that were maintained in synchronized cultured primary skeletal myotubes in vitro. Oscillating lipid metabolites were not limited to energy-controlling storage lipids such as triglycerides but also comprised membrane and signaling lipids from different cellular compartments [167]. RNAseq analyses suggested that key enzymes regulating lipid biosynthesis in the skeletal muscle exhibited rhythmic profiles [165]. In the adipose tissue White adipose tissue (WAT) also plays a crucial role in regulating glucose homeostasis and represents a major site of glucose utilization, energy storage, thermogenesis, and adipokine secretion. An increase in the white adipose tissue mass, in particular through the accumulation of visceral fat, is

Circadian Regulation of Metabolism

associated with an elevated risk of development of insulin resistance, cardiovascular diseases, and the metabolic syndrome [169]. The circadian clock controls the rate of triacylglycerides lipolysis in WAT by directly modulating the expression of lipase genes [170]. Moreover, the expression of peroxisome proliferator-activated receptor g (PPARg), which is essential for the synthesis and storage of fatty acids, is rhythmically driven by PERIOD 2 and 3 proteins [171]. PER2 inhibits the transcriptional activity of PPARg [172], and PER3, in complex with BMAL1, decreases adipogenesis in preadipocytes [173]. Concomitantly, the adipocyte-specific deletion of Bmal1 in mice results in obesity due to changes in feeding behavior and a shift toward energy storage associated with reduced polyunsaturated fatty acid metabolism and dysleptinemia [174,175]. WAT plays an important endocrine role in the body because it secretes adipokine molecules. Depending on the nutritional status of the body, adipokine levels vary throughout the day in rodents and humans [169,176,177]. Leptin is a key regulator of the energy balance of the body because it indirectly suppresses appetite by targeting NPY/AgRP and arcuate proopiomelanocortin neurons that are involved in regulating food intake. Indeed, systemic leptin levels increase and decrease rapidly upon feeding and fasting, respectively, in an SCN-dependent manner [178,179]. Leptin has been shown to be indirectly regulated by CLOCK-BMAL1 in a cellautonomous manner in AgRP neurons [102,174]. Similar to the skeletal muscle, adipose tissue also exhibits a circadian rhythmicity of insulin sensitivity [180]. The brown adipose tissue (BAT) is a major regulator of energy expenditure and thermogenesis, as it converts ATP into heat by uncoupling lipid oxidation in the mitochondria. In this tissue, REVERBa is required to maintain the body temperature rhythms by repressing Ucp1 expression [86] and by increasing the circadian changes in the level of expression of the genes controlling de novo lipogenesis during chronic cold exposure [181]. Moreover, glucose and fatty acid uptake display rhythmic patterns in BAT in mice [182,183]. In the intestine In the intestine, lipid transfer and absorption by enterocytes is regulated by the circadian clock system [184]. Furthermore, the deadenylase, Nocturnin (Ccrn4l), which is essential for lipid absorption and secretion in the intestine, exhibits circadian rhythmic expression [185]. The mechanism linking Nocturnin to lipid metabolism has not been completely elucidated and it is thought to be independent of its deadenylase activity. The recent discovery that Nocturnin participates in the mechanism regulating

3687 NADP(H) provides a novel mechanistic link between the circadian clock and the role of Nocturnin in lipid homeostasis [186]. GLP1 is rhythmically secreted by enteroendocrine L-cells and plays an important role in regulating glucose homeostasis; its oscillatory profile coincides with the expression of Bmal1 [111,187]. Notably, Bmal1 KO resulted in the impaired release of GLP1, with palmitate treatment leading to a decrease in Bmal1 expression, impaired mitochondrial function, and decreased GLP1 secretion [188].

The Circadian Clock System and Human Metabolic Diseases According to epidemiological and molecular studies, human physiology and behavior are subject to daily oscillations. Indeed, circadian rhythms of cardiovascular, endocrine, digestive, and immune functions, as well as metabolic and detoxification processes, have been reported in humans [169,177,189e192]. Concordantly, large-scale metabolomics and lipidomics screens conducted for 24 h using human sera, saliva, and tissue samples revealed that a significant proportion of metabolites exhibit rhythmic profiles [142,167,193e196]. Cell-autonomous clocks, which have recently been identified in various human tissues, play a primordial role in this regulatory mechanism [144,155,197e200]. Furthermore, alterations in the circadian clock machinery have been observed concomitantly with the development of various human pathologies such as cardiovascular, metabolic, and immune diseases and cancer (Fig. 2 [163,197,201e208]). Perturbations in the circadian clocks are a hallmark of human metabolic diseases Glucose homeostasis is subject to tight regulation by the human circadian system. Indeed, glucose tolerance depends on the time of the day, and it is higher in the morning than in the evening [209]. Moreover, blood insulin levels, pancreatic b-cell glucose sensitivity, and skeletal muscle insulin sensitivity oscillate throughout the day in healthy humans [210e212]. The development of metabolic diseases, including obesity and type 2 diabetes (T2D), is associated with perturbed rhythms of the molecular clocks in human pancreatic islets, concomitant with disruption of insulin and glucagon secretion [213]. Moreover, disruption of insulin sensitivity [163,206,214,215], alterations in the transcriptional landscape in the white adipose tissue [207,208], and a blunted rhythm of clock gene expression in circulating leucocytes [216] have been reported in T2D patients. Notably, polymorphisms in the core clock genes are linked to defects in

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Circadian Regulation of Metabolism

Fig. 2. Human pathologies are associated with circadian misalignment between the internal body clocks and environmental cycles. Chronic sleep deprivation, shift work, altered eating patterns, and social jetlag are the leading causes of the misalignment of the internal circadian system from the external cues. In turn, chronic circadian misalignment leads to various pathologies. Metabolic disorders, such as obesity, fatty liver disease, and type 2 diabetes, along with cardiovascular and inflammatory diseases and cancer, were reported to be associated with circadian misalignment in humans. Notably, alterations in sleep and eating patterns lead to the development of circadian misalignment and are subsequently further exacerbated by this condition, thus representing both a cause and an effect.

glucose homeostasis and obesity [217e220], as well as the susceptibility to T2D [221,222]. The role of melatonin in regulating glucose metabolism has been extensively explored during the last few decades, with somewhat controversial conclusions drawn from different studies. This controversy regarding the beneficial or deleterious effects of this hormone on the glucose tolerance and development of T2D may be attributed to the differences in the times of day at which these different studies were conducted. A highly oscillatory pattern of melatonin secretion has been observed that peaks during the night and decreases to very low levels during the day [223]. Mutations in the MTNR1B variant, encoding the melatonin receptor MT2, are associated with an increased risk of T2D [224e227]. Concordantly, altered rhythmic changes in melatonin concentrations have been reported in obese patients with T2D compared to BMI-matched nondiabetic subjects [228]. Importantly, although no significant differences in the oscillations of the core clock components were detected in primary skin fibroblasts or myotubes derived from lean subjects, obese subjects, and subjects with T2D [201,229], an inverse correlation between the Bmal1 oscillation period length mea-

sured in primary fibroblasts and HbA1c values in the blood has been reported within the T2D group, suggesting a link between T2D progression and the properties of individual core clock components [201]. In addition, transcriptomic screens of nonsynchronized human islets from donors with T2D revealed changes in the expression of the core clock transcripts Per2, Per3, and Cry2 [230,231]. Taken together, accumulating evidence from recent studies underscores an important perspective for the potential application of the core clock components as biomarkers for the diagnosis a nd the pro g r es s i o n o f h u m an di s ea s e s [197,201e204,238e242]. Deleterious effects of circadian misalignments on human metabolism The modern lifestyle in our 24/7 society implies exposure to artificial light during the night time, short sleep durations, and late meal times that together lead to desynchronization between the internal circadian system and external Zeitgebers, a phenomenon dubbed circadian misalignment (Fig. 2). Increasing evidence from human studies highlights a link between chronic circadian misalignment and

Circadian Regulation of Metabolism

cardiovascular problems, metabolic diseases, cancer, inflammatory and liver pathologies (Fig. 2 [8,243e245]). Indeed, observational studies revealed an increased risk of developing T2D for shift workers that was associated with the number of night shifts per month [246]. Subjects with a late chronotype are likely at increased risk of developing T2D and metabolic disorders [247,248]. Concordantly, patients with T2D presenting the late chronotype exhibited worse glycemic control than their counterparts with T2D presenting the early chronotype [249e251]. Along with the “real-life” studies, well-controlled constant routine protocols have been applied to assess the effect of a circadian disruption on human health. Based on constant routine laboratory studies, chronic sleep deprivation in healthy volunteers proved sufficient to lower glucose tolerance [252,253] and reduce insulin sensitivity [254,255]. Similarly, circadian misalignment induced by a rapid day-night switch results in the development of insulin resistance in the skeletal muscle and disturbed gene expression patterns, suggesting disturbed substrate partitioning [206]. Notably, the observed deleterious effect of insufficient sleep was not compensated by ad libitum weekend recovery sleep [256]. Similarly, glucose tolerance and metabolite rhythms were impaired in individuals subjected to experimental circadian misalignment [206,212,257e259]. Moreover, the phase-shift response of circulating plasma metabolites to the simulated night shifts exhibited a large interindividual variation and was mainly driven by sleep-wake and feeding-fasting cycles, rather than by the endogenous circadian system [260]. Over the last decade, it has become increasingly clear that not only the composition of diet, but also the “misalignment” of the timing of meals with internal body clocks, strongly affects the effectiveness of weight loss and plasma lipid profiles [261e265]. Indeed, a late lunch (4.30 p.m.) or generally late eating (all meals eaten 5.5 he15.5 h after the wake time) led to metabolic dysfunction. By contrast, an earlier eating pattern, with the meals eaten 0.5 he10.5 h after wake time, exerted a protective effect on glucose tolerance and energy expenditure [266,267]. Accordingly, food consumption restricted to early hours in men with prediabetes who ate all their calories within an early 6-h window (with the last meal consumed before 3 p.m.) led to improved glucose tolerance, a reduction in the blood triglyceride levels, better sleep quality, and reduced feelings of hunger [268]. These strikingly distinct metabolic consequences of the same meal consumed at different times of day prompted the hypothesis that temporal coordination between the eating pattern and internal metabolic clocks is as important for the metabolic health as the composition of the diet [266,269e271]. Concordantly, restriction of the feeding time to the active phase proved

3689 beneficial for improving metabolic health in rodents [272,273] and humans [274,275]. Moreover, intermittent periods of prolonged fasting (greater than 16 h) improved metabolic health [268,276] and promoted weight loss in obese and overweight human subjects [277e280].

Perspectives: Boosting the Circadian Clocks to Improve the Quality of Life Based on the strong association between disturbed circadian behaviors and metabolic disorders, “realignment” of circadian sleep-wake cycles with the feeding rhythm potentially represents a sensible approach to prevent and treat metabolic pathologies. Exposure to bright light during the daytime may improve metabolic health by sustaining robust circadian rhythms. Indeed, morning light therapy for several weeks improves the insulin sensitivity of patients with T2D [281,282]. Time-restricted eating aligned with the individual chronotype, as well as scheduled exercise, represents additional potent strategies that increase the circadian amplitude [93,96,262]. These nonmedicinal lifestyle interventions may represent a powerful approach for attenuating the epidemically increasing incidence of metabolic diseases. Importantly, a comparison of the data sets derived from serial tissue biopsies obtained from human volunteers in vivo and corresponding primary cultured cells synchronized in vitro revealed a substantial similarity between the subsets of transcripts and lipid metabolites oscillating in vivo and in vitro in skeletal muscle tissue and primary myotubes [165,167,232]. These findings further emphasize that primary cell cultures synchronized in vitro represent a powerful tool for molecular studies of the human peripheral clocks and their functional outputs [8,168,200,233,234]. Along with developing in vitro primary culture models, minimally invasive in vivo methods for studying molecular clocks and metabolic cycles in humans based on blood sampling at a single time point [235] and magnetic resonance imaging [236,237] hold promise for future circadian studies in humans. The emergence of circadian medicine, also dubbed chronopharmacology, represents a highly promising and advanced tool for disease management [283]. Because the pharmacological targets often exhibit rhythmic oscillations, the mechanisms of action of medications can be potentiated by timing their delivery, while their toxicity can be reduced using the same strategy. Indeed, a timed pharmacological inhibition of the CCL2-CCR2 axis in rodents reduces atherosclerosis [284], and the effects of timed administration of glucose and lipidlowering drugs hold promise for treatment [285e287].

3690

Circadian Regulation of Metabolism

Finally, a pharmacological approach for restoring the attenuated activity of molecular clocks has emerged from the identification and characterization of clock modulator molecules [288]. Small molecules targeting REV-ERBs and CRYs represent promising candidates for the treatment of metabolic disorders due to their beneficial effects on glucose metabolism [289e291]. The ROR agonist nobiletin, which is extracted from lemon peel, exerted remarkable beneficial metabolic effects along with an increase in the amplitude and thus showed important therapeutic potential [292,293].

ter; HFD, high-fat diet; HSF1, heat-shock factor 1; HIF, hypoxia-inducible factor; IL6, interleukin 6; MCP1, monocyte chemoattractant protein-1; NAD, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyltransferase; OGT, O-GlcNAc transferase; PARP1, poly(ADP-ribose) polymerase 1; PCK1, phosphoenolpyruvate carboxykinase 1; PPAR, peroxisome proliferator-activated receptor; SCN, suprachiasmatic nucleus; SIRT, sirtuin; SREBP, sterol regulatory elementbinding transcription factor; T2D, type 2 diabetes; TAGs, triacylglycerides; mTOR, mammalian target of rapamycin; WAT, white adipose tissue.

References

Acknowledgments The authors thank Laurence Zulianello for preparing the artwork. This work was funded by Swiss National Science Foundation grants 31003A_166700/1 and 310030_184708/1, the Vontobel Foundation, the Novartis Consumer Health Foundation, Bo and Kerstin Hjelt Foundation for type 2 diabetes, Swiss Life Foundation, and the Olga Mayenfisch Foundation to CD, and by a SSED/ SGED Young Investigator grant to FS.

Conflict of interest statement None. Received 16 December 2019; Received in revised form 16 January 2020; Accepted 16 January 2020 Available online 26 January 2020 Keywords: circadian clock system; metabolic rhythms; circadian misalignment; human pathologies

Abbreviations used: AANAT, arylalkylamine N-acetyltransferase; Acss3, acylCoA synthetase short-chain family member 3; AMPK, AMP-activated protein kinase; BAT, brown adipose tissue; BMAL1, brain and muscle ARNT-like 1; BMI, body mass index; CCGs, clock-controlled genes; CIRPB, cold-inducible RNA-binding protein 1; CLOCK, circadian locomotor output cycles kaput; CREB, cAMP response elementbinding protein; Elovl, elongation of very long chain fatty acids; FAD, flavin adenine dinucleotide; GlcNAc, Nacetylglucosamine; GSK3, glycogen synthase kinase 3; GLP1, glucagon like peptide-1; GLUT, glucose transpor-

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