RESUMO
The circadian clock is encoded by a negative transcriptional feedback loop that coordinates physiology and behavior through molecular programs that remain incompletely understood. Here, we reveal rhythmic genome-wide alternative splicing (AS) of pre-mRNAs encoding regulators of peptidergic secretion within pancreatic ß cells that are perturbed in Clock-/- and Bmal1-/- ß-cell lines. We show that the RNA-binding protein THRAP3 (thyroid hormone receptor-associated protein 3) regulates circadian clock-dependent AS by binding to exons at coding sequences flanking exons that are more frequently skipped in clock mutant ß cells, including transcripts encoding Cask (calcium/calmodulin-dependent serine protein kinase) and Madd (MAP kinase-activating death domain). Depletion of THRAP3 restores expression of the long isoforms of Cask and Madd, and mimicking exon skipping in these transcripts through antisense oligonucleotide delivery in wild-type islets reduces glucose-stimulated insulin secretion. Finally, we identify shared networks of alternatively spliced exocytic genes from islets of rodent models of diet-induced obesity that significantly overlap with clock mutants. Our results establish a role for pre-mRNA alternative splicing in ß-cell function across the sleep/wake cycle.
Assuntos
Processamento Alternativo , Relógios Circadianos/genética , Exocitose , Glucose/metabolismo , Secreção de Insulina/genética , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/fisiologia , Animais , Proteínas CLOCK/genética , Proteínas CLOCK/fisiologia , Células Cultivadas , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/genética , Proteínas Adaptadoras de Sinalização de Receptores de Domínio de Morte/metabolismo , Fatores de Troca do Nucleotídeo Guanina/genética , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Guanilato Quinases/genética , Guanilato Quinases/metabolismo , Homeostase , Células Secretoras de Insulina/metabolismo , Ilhotas Pancreáticas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas Nucleares/fisiologia , Obesidade/genética , Obesidade/metabolismo , Proteína 25 Associada a Sinaptossoma/genética , Proteína 25 Associada a Sinaptossoma/metabolismo , Fatores de Transcrição/fisiologiaRESUMO
The mammalian circadian clock is encoded by an autoregulatory transcription feedback loop that drives rhythmic behavior and gene expression in the brain and peripheral tissues. Transcriptomic analyses indicate cell type-specific effects of circadian cycles on rhythmic physiology, although how clock cycles respond to environmental stimuli remains incompletely understood. Here, we show that activation of the inducible transcription factor NF-κB in response to inflammatory stimuli leads to marked inhibition of clock repressors, including the Period, Cryptochrome, and Rev-erb genes, within the negative limb. Furthermore, activation of NF-κB relocalizes the clock components CLOCK/BMAL1 genome-wide to sites convergent with those bound by NF-κB, marked by acetylated H3K27, and enriched in RNA polymerase II. Abrogation of NF-κB during adulthood alters the expression of clock repressors, disrupts clock-controlled gene cycles, and impairs rhythmic activity behavior, revealing a role for NF-κB in both unstimulated and activated conditions. Together, these data highlight NF-κB-mediated transcriptional repression of the clock feedback limb as a cause of circadian disruption in response to inflammation.
Assuntos
Ritmo Circadiano/genética , NF-kappa B/fisiologia , Fatores de Transcrição ARNTL/metabolismo , Animais , Comportamento Animal , Proteínas CLOCK/metabolismo , Linhagem Celular , Cromatina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NF-kappa B/metabolismo , Proteínas Repressoras/metabolismo , Transcrição GênicaRESUMO
The molecular clock maintains energy constancy by producing circadian oscillations of rate-limiting enzymes involved in tissue metabolism across the day and night. During periods of feeding, pancreatic islets secrete insulin to maintain glucose homeostasis, and although rhythmic control of insulin release is recognized to be dysregulated in humans with diabetes, it is not known how the circadian clock may affect this process. Here we show that pancreatic islets possess self-sustained circadian gene and protein oscillations of the transcription factors CLOCK and BMAL1. The phase of oscillation of islet genes involved in growth, glucose metabolism and insulin signalling is delayed in circadian mutant mice, and both Clock and Bmal1 (also called Arntl) mutants show impaired glucose tolerance, reduced insulin secretion and defects in size and proliferation of pancreatic islets that worsen with age. Clock disruption leads to transcriptome-wide alterations in the expression of islet genes involved in growth, survival and synaptic vesicle assembly. Notably, conditional ablation of the pancreatic clock causes diabetes mellitus due to defective beta-cell function at the very latest stage of stimulus-secretion coupling. These results demonstrate a role for the beta-cell clock in coordinating insulin secretion with the sleep-wake cycle, and reveal that ablation of the pancreatic clock can trigger the onset of diabetes mellitus.
Assuntos
Fatores de Transcrição ARNTL/genética , Proteínas CLOCK/genética , Ritmo Circadiano/fisiologia , Diabetes Mellitus/metabolismo , Insulina/sangue , Ilhotas Pancreáticas/metabolismo , Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/metabolismo , Envelhecimento/genética , Envelhecimento/patologia , Animais , Glicemia/análise , Glicemia/metabolismo , Proteínas CLOCK/deficiência , Proteínas CLOCK/metabolismo , Proliferação de Células , Tamanho Celular , Sobrevivência Celular , Ritmo Circadiano/genética , Diabetes Mellitus/genética , Perfilação da Expressão Gênica , Intolerância à Glucose/genética , Teste de Tolerância a Glucose , Técnicas In Vitro , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/patologia , Camundongos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Fenótipo , Sono/genética , Sono/fisiologia , Vesículas Sinápticas/metabolismo , Vigília/genética , Vigília/fisiologiaRESUMO
Interactions between lineage-determining and activity-dependent transcription factors determine single-cell identity and function within multicellular tissues through incompletely known mechanisms. By assembling a single-cell atlas of chromatin state within human islets, we identified ß cell subtypes governed by either high or low activity of the lineage-determining factor pancreatic duodenal homeobox-1 (PDX1). ß cells with reduced PDX1 activity displayed increased chromatin accessibility at latent nuclear factor κB (NF-κB) enhancers. Pdx1 hypomorphic mice exhibited de-repression of NF-κB and impaired glucose tolerance at night. Three-dimensional analyses in tandem with chromatin immunoprecipitation (ChIP) sequencing revealed that PDX1 silences NF-κB at circadian and inflammatory enhancers through long-range chromatin contacts involving SIN3A. Conversely, Bmal1 ablation in ß cells disrupted genome-wide PDX1 and NF-κB DNA binding. Finally, antagonizing the interleukin (IL)-1ß receptor, an NF-κB target, improved insulin secretion in Pdx1 hypomorphic islets. Our studies reveal functional subtypes of single ß cells defined by a gradient in PDX1 activity and identify NF-κB as a target for insulinotropic therapy.
Assuntos
Células Secretoras de Insulina , NF-kappa B , Animais , Humanos , Camundongos , Cromatina/metabolismo , Genes Homeobox , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Células Secretoras de Insulina/metabolismo , NF-kappa B/metabolismoRESUMO
Circadian clocks maintain periodicity in internal cycles of behavior, physiology, and metabolism, enabling organisms to anticipate the 24-h rotation of the Earth. In mammals, circadian integration of metabolic systems optimizes energy harvesting and utilization across the light/dark cycle. Disruption of clock genes has recently been linked to sleep disorders and to the development of cardiometabolic disease. Conversely, aberrant nutrient signaling affects circadian rhythms of behavior. This chapter reviews the emerging relationship between the molecular clock and metabolic systems and examines evidence that circadian disruption exerts deleterious consequences on human health.
Assuntos
Relógios Circadianos/fisiologia , Animais , Ritmo Circadiano , Humanos , Luz , Camundongos , NAD/metabolismo , Fenótipo , Polimorfismo Genético , Receptores Citoplasmáticos e Nucleares/fisiologia , Transcrição GênicaRESUMO
Misalignment of feeding rhythms with the light-dark cycle leads to disrupted peripheral circadian clocks and obesity. Conversely, restricting feeding to the active period mitigates metabolic syndrome through mechanisms that remain unknown. We found that genetic enhancement of adipocyte thermogenesis through ablation of the zinc finger protein 423 (ZFP423) attenuated obesity caused by consumption of a high-fat diet during the inactive (light) period by increasing futile creatine cycling in mice. Circadian control of adipocyte creatine metabolism underlies the timing of diet-induced thermogenesis, and enhancement of adipocyte circadian rhythms through overexpression of the clock activator brain and muscle Arnt-like protein-1 (BMAL1) ameliorated metabolic complications during diet-induced obesity. These findings uncover rhythmic creatine-mediated thermogenesis as an essential mechanism that drives metabolic benefits during time-restricted feeding.
Assuntos
Adipócitos , Relógios Circadianos , Ritmo Circadiano , Creatina , Proteínas de Ligação a DNA , Dieta Hiperlipídica , Obesidade , Termogênese , Fatores de Transcrição , Animais , Camundongos , Adipócitos/metabolismo , Fatores de Transcrição ARNTL/genética , Creatina/metabolismo , Obesidade/etiologia , Obesidade/prevenção & controle , Termogênese/genética , Fatores de Tempo , Dieta Hiperlipídica/efeitos adversos , Proteínas de Ligação a DNA/genética , Fatores de Transcrição/genética , Camundongos KnockoutRESUMO
The mammalian circadian clock drives daily oscillations in physiology and behavior through an autoregulatory transcription feedback loop present in central and peripheral cells. Ablation of the core clock within the endocrine pancreas of adult animals impairs the transcription and splicing of genes involved in hormone exocytosis and causes hypoinsulinemic diabetes. Here, we developed a genetically sensitized small-molecule screen to identify druggable proteins and mechanistic pathways involved in circadian ß-cell failure. Our approach was to generate ß-cells expressing a nanoluciferase reporter within the proinsulin polypeptide to screen 2640 pharmacologically active compounds and identify insulinotropic molecules that bypass the secretory defect in CRISPR-Cas9-targeted clock mutant ß-cells. We validated hit compounds in primary mouse islets and identified known modulators of ligand-gated ion channels and G-protein-coupled receptors, including the antihelmintic ivermectin. Single-cell electrophysiology in circadian mutant mouse and human cadaveric islets revealed ivermectin as a glucose-dependent secretagogue. Genetic, genomic, and pharmacological analyses established the P2Y1 receptor as a clock-controlled mediator of the insulinotropic activity of ivermectin. These findings identify the P2Y1 purinergic receptor as a diabetes target based upon a genetically sensitized phenotypic screen.
Circadian rhythms 'inbuilt' 24-hour cycles control many aspects of behaviour and physiology. In mammals, they operate in nearly all tissues, including those involved in glucose metabolism. Recent studies have shown that mice with faulty genes involved in circadian rhythms, the core clock genes, can develop diabetes. Diabetes arises when the body struggles to regulate blood sugar levels. In healthy individuals, the hormone insulin produced by beta cells in the pancreas regulates the amount of sugar in the blood. But when beta cells are faulty and do not generate sufficient insulin levels, or when insulin lacks the ability to stimulate cells to take up glucose, diabetes can develop. Marcheva, Weidemann, Taguchi et al. wanted to find out if diabetes caused by impaired clock genes could be treated by targeting pathways regulating the secretion of insulin. To do so, they tested over 2,500 potential drugs on genetically modified beta cells with faulty core clock genes. They further screened the drugs on mice with the same defect in their beta cells. Marcheva et al. identified one potential compound, the anti-parasite drug ivermectin, which was able to restore the secretion of insulin. When ivermectin was applied to both healthy mice and mice with faulty beta cells, the drug improved the control over glucose levels by activating a specific protein receptor that senses molecules important for storing and utilizing energy. The findings reveal new drug targets for treating forms of diabetes associated with deregulation of the pancreatic circadian clock. The drug screening strategy used in the study may also be applied to reveal mechanisms underlying other conditions associated with disrupted circadian clocks, including sleep loss and jetlag.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/farmacologia , Ilhotas Pancreáticas/metabolismo , Receptores Purinérgicos P2Y1/metabolismo , Fatores de Transcrição ARNTL , Animais , Linhagem Celular , Relógios Circadianos , Ritmo Circadiano , Criptocromos/genética , Criptocromos/metabolismo , Diabetes Mellitus/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Ensaios de Triagem em Larga Escala , Homeostase , Humanos , Insulina/metabolismo , Células Secretoras de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
The hypothalamic neuronal circuits that modulate energy homeostasis become mature and functional during early postnatal life. However, the molecular mechanism underlying this developmental process remains largely unknown. Here we use a mouse genetic approach to investigate the role of gamma-protocadherins (Pcdh-gammas) in hypothalamic neuronal circuits. First, we show that rat insulin promoter (RIP)-Cre conditional knockout mice lacking Pcdh-gammas in a broad subset of hypothalamic neurons are obese and hyperphagic. Second, specific deletion of Pcdh-gammas in anorexigenic proopiomelanocortin (POMC) expressing neurons also leads to obesity. Using cell lineage tracing, we show that POMC and RIP-Cre expressing neurons do not overlap but interact with each other in the hypothalamus. Moreover, excitatory synaptic inputs are reduced in Pcdh-gamma deficient POMC neurons. Genetic evidence from both knockout models shows that Pcdh-gammas can regulate POMC neuronal function autonomously and non-autonomously through cell-cell interaction. Taken together, our data demonstrate that Pcdh-gammas regulate the formation and functional integrity of hypothalamic feeding circuitry in mice.
Assuntos
Caderinas/fisiologia , Comportamento Alimentar/fisiologia , Hipotálamo/fisiologia , Animais , Proteínas Relacionadas a Caderinas , Caderinas/genética , Linhagem da Célula , Metabolismo Energético , Hipotálamo/citologia , Imuno-Histoquímica , Ilhotas Pancreáticas/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microscopia Imunoeletrônica , Neurônios/citologia , Reação em Cadeia da PolimeraseRESUMO
In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+, a cosubstrate of the class III histone deacetylase sirtuin 1 (SIRT1) that associates with clock transcription factors. Although NAD+ also participates in redox reactions, the extent to which NAD(H) couples nutrient state with circadian transcriptional cycles remains unknown. Here we show that nocturnal animals subjected to time-restricted feeding of a calorie-restricted diet (TRF-CR) only during night-time display reduced body temperature and elevated hepatic NADH during daytime. Genetic uncoupling of nutrient state from NADH redox state through transduction of the water-forming NADH oxidase from Lactobacillus brevis (LbNOX) increases daytime body temperature and blood and liver acyl-carnitines. LbNOX expression in TRF-CR mice induces oxidative gene networks controlled by brain and muscle Arnt-like protein 1 (BMAL1) and peroxisome proliferator-activated receptor alpha (PPARα) and suppresses amino acid catabolic pathways. Enzymatic analyses reveal that NADH inhibits SIRT1 in vitro, corresponding with reduced deacetylation of SIRT1 substrates during TRF-CR in vivo. Remarkably, Sirt1 liver nullizygous animals subjected to TRF-CR display persistent hypothermia even when NADH is oxidized by LbNOX. Our findings reveal that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.
Assuntos
Metabolismo Energético , Jejum , NAD/metabolismo , Sirtuína 1/genética , Sirtuína 1/metabolismo , Transcrição Gênica , Aminoácidos/metabolismo , Animais , Temperatura Corporal , Ritmo Circadiano , Dieta , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Fígado/metabolismo , Camundongos , Fatores de TranscriçãoRESUMO
The alignment of fasting and feeding with the sleep/wake cycle is coordinated by hypothalamic neurons, though the underlying molecular programs remain incompletely understood. Here, we demonstrate that the clock transcription pathway maximizes eating during wakefulness and glucose production during sleep through autonomous circadian regulation of NPY/AgRP neurons. Tandem profiling of whole-cell and ribosome-bound mRNAs in morning and evening under dynamic fasting and fed conditions identified temporal control of activity-dependent gene repertoires in AgRP neurons central to synaptogenesis, bioenergetics, and neurotransmitter and peptidergic signaling. Synaptic and circadian pathways were specific to whole-cell RNA analyses, while bioenergetic pathways were selectively enriched in the ribosome-bound transcriptome. Finally, we demonstrate that the AgRP clock mediates the transcriptional response to leptin. Our results reveal that time-of-day restriction in transcriptional control of energy-sensing neurons underlies the alignment of hunger and food acquisition with the sleep/wake state.
Assuntos
Proteína Relacionada com Agouti/metabolismo , Relógios Circadianos/genética , Ritmo Circadiano/genética , Fome/fisiologia , Neurônios/metabolismo , Transcrição Gênica/genética , Proteína Relacionada com Agouti/genética , Animais , Ingestão de Alimentos/fisiologia , Jejum/fisiologia , Redes Reguladoras de Genes , Glucose/metabolismo , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transdução de Sinais/genética , Sono/fisiologia , Transcriptoma , Vigília/fisiologiaRESUMO
The mammalian circadian clock plays a central role in the temporal coordination of physiology across the 24-h light-dark cycle. A major function of the clock is to maintain energy constancy in anticipation of alternating periods of fasting and feeding that correspond with sleep and wakefulness. While it has long been recognized that humans exhibit robust variation in glucose tolerance and insulin sensitivity across the sleep-wake cycle, experimental genetic analysis has now revealed that the clock transcription cycle plays an essential role in insulin secretion and metabolic function within pancreatic beta cells. This review addresses how studies of the beta cell clock may elucidate the etiology of subtypes of diabetes associated with circadian and sleep cycle disruption, in addition to more general forms of the disease.
Assuntos
Ritmo Circadiano/genética , Diabetes Mellitus Tipo 2/fisiopatologia , Células Secretoras de Insulina/fisiologia , Insulina/metabolismo , Transcrição Gênica , Animais , Relógios Circadianos , Diabetes Mellitus Tipo 2/genética , Jejum , Genômica , Humanos , Resistência à Insulina/genética , Secreção de Insulina , Camundongos , Fotoperíodo , Sono/fisiologia , VigíliaRESUMO
The mammalian transcription factors CLOCK and BMAL1 are essential components of the molecular clock that coordinate behavior and metabolism with the solar cycle. Genetic or environmental perturbation of circadian cycles contributes to metabolic disorders including type 2 diabetes. To study the impact of the cell-autonomous clock on pancreatic ß cell function, we examined pancreatic islets from mice with either intact or disrupted BMAL1 expression both throughout life and limited to adulthood. We found pronounced oscillation of insulin secretion that was synchronized with the expression of genes encoding secretory machinery and signaling factors that regulate insulin release. CLOCK/BMAL1 colocalized with the pancreatic transcription factor PDX1 within active enhancers distinct from those controlling rhythmic metabolic gene networks in liver. We also found that ß cell clock ablation in adult mice caused severe glucose intolerance. Thus, cell type-specific enhancers underlie the circadian control of peripheral metabolism throughout life and may help to explain its dysregulation in diabetes.
Assuntos
Ritmo Circadiano/genética , Elementos Facilitadores Genéticos/fisiologia , Regulação da Expressão Gênica , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Proteínas CLOCK/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Exocitose/genética , Intolerância à Glucose , Proteínas de Homeodomínio/metabolismo , Humanos , Secreção de Insulina , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Transativadores/metabolismo , Transcrição GênicaRESUMO
Many of our behavioral and physiological processes display daily oscillations that are under the control of the circadian clock. The core molecular clock network is present in both the brain and peripheral tissues and is composed of a complex series of interlocking transcriptional/translational feedback loops that oscillate with a periodicity of ~24 h. Recent evidence has implicated NAD(+) biosynthesis and the sirtuin family of NAD(+)-dependent protein deacetylases as part of a novel feedback loop within the core clock network, findings which underscore the importance of taking circadian timing into consideration when designing and interpreting metabolic studies, particularly in regard to sirtuin biology. Thus, this chapter introduces both in vivo and in vitro circadian methods to analyze various sirtuin-related endpoints across the light-dark cycle and discusses the transcriptional, biochemical, and physiological outputs of the clock.
Assuntos
Relógios Circadianos/fisiologia , Ritmo Circadiano/fisiologia , NAD/metabolismo , Sirtuínas/metabolismo , Animais , Retroalimentação Fisiológica , Locomoção , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Sirtuínas/genética , Transcrição GênicaRESUMO
Circadian clocks are self-sustained cellular oscillators that synchronize oxidative and reductive cycles in anticipation of the solar cycle. We found that the clock transcription feedback loop produces cycles of nicotinamide adenine dinucleotide (NAD(+)) biosynthesis, adenosine triphosphate production, and mitochondrial respiration through modulation of mitochondrial protein acetylation to synchronize oxidative metabolic pathways with the 24-hour fasting and feeding cycle. Circadian control of the activity of the NAD(+)-dependent deacetylase sirtuin 3 (SIRT3) generated rhythms in the acetylation and activity of oxidative enzymes and respiration in isolated mitochondria, and NAD(+) supplementation restored protein deacetylation and enhanced oxygen consumption in circadian mutant mice. Thus, circadian control of NAD(+) bioavailability modulates mitochondrial oxidative function and organismal metabolism across the daily cycles of fasting and feeding.
Assuntos
Relógios Circadianos/fisiologia , Metabolismo Energético , Mitocôndrias Hepáticas/metabolismo , NAD/metabolismo , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Acetilação , Animais , Relógios Circadianos/genética , Jejum , Metabolismo dos Lipídeos , Fígado/metabolismo , Camundongos , Camundongos Knockout , Oxirredução , Consumo de Oxigênio , Sirtuína 3/genética , Sirtuína 3/metabolismoRESUMO
The circadian system synchronizes behavioral and physiologic processes with daily changes in the external light-dark cycle, optimizing energetic cycles with the rising and setting of the sun. Molecular clocks are organized hierarchically, with neural clocks orchestrating the daily switch between periods of feeding and fasting, and peripheral clocks generating 24h oscillations of energy storage and utilization. Recent studies indicate that clocks respond to nutrient signals and that a high-fat diet influences the period of locomotor activity under free-running conditions, a core property of the clock. A major goal is to identify the molecular basis for the reciprocal relation between metabolic and circadian pathways. Here the role of peptidergic hormones and macromolecules as nutrient signals integrating circadian and metabolic systems is highlighted.
Assuntos
Relógios Circadianos/fisiologia , Animais , Dieta Hiperlipídica , Humanos , Atividade Motora/fisiologiaRESUMO
The molecular clock controls 24-hour cycles of behavioral and physiological processes across the day-night cycle. Disruption of circadian rhythmicity has been implicated in the pathogenesis of several diseases, including the metabolic syndrome, although the role of clock genes in these disorders is still not well understood. Studies of the etiology of diabetes in circadian mutant mice have revealed a novel role for the clock in pancreatic ß-cell insulin secretion, suggesting that a major cellular function of the circadian network involves control of protein exocytosis.
RESUMO
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.
Assuntos
Ritmo Circadiano/fisiologia , Metabolismo Energético/fisiologia , Sono/fisiologia , Animais , Encéfalo/fisiologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Ritmo Circadiano/efeitos da radiação , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Dieta , Gorduras na Dieta/efeitos adversos , Glucose/metabolismo , Homeostase/fisiologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Camundongos , Camundongos Mutantes , Rede Nervosa/fisiologia , Neuropeptídeos/fisiologia , Obesidade/fisiopatologia , Orexinas , Transdução de Sinais , Privação do Sono/fisiopatologia , Transtornos do Sono do Ritmo Circadiano/fisiopatologiaRESUMO
The circadian system is a key integrator of behavior and metabolism that synchronizes physiological processes with the rotation of the Earth on its axis. In mammals, the clock is present not only within the central pacemaker neurons of the hypothalamus, but also within extra-suprachiasmatic nucleus (SCN) regions of brain and nearly all peripheral tissues. Recent evidence suggests that the complex feedback networks that encompass both the circadian and metabolic systems are intimately intertwined and that disruption of either system leads to reciprocal disturbances in the other. We anticipate that improved understanding of the interconnections between the circadian and metabolic networks will open new windows on the treatment of sleep and metabolic disorders, including diabetes mellitus and obesity.
Assuntos
Transtornos Cronobiológicos/complicações , Transtornos Cronobiológicos/fisiopatologia , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Ritmo Circadiano , Doenças Metabólicas/complicações , Doenças Metabólicas/fisiopatologia , Modelos Biológicos , Animais , Metabolismo Energético , HumanosRESUMO
The circadian clock is encoded by a transcription-translation feedback loop that synchronizes behavior and metabolism with the light-dark cycle. Here we report that both the rate-limiting enzyme in mammalian nicotinamide adenine dinucleotide (NAD+) biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), and levels of NAD+ display circadian oscillations that are regulated by the core clock machinery in mice. Inhibition of NAMPT promotes oscillation of the clock gene Per2 by releasing CLOCK:BMAL1 from suppression by SIRT1. In turn, the circadian transcription factor CLOCK binds to and up-regulates Nampt, thus completing a feedback loop involving NAMPT/NAD+ and SIRT1/CLOCK:BMAL1.