Integration of Feeding Time and Glucose Metabolism by the Circadian Gene Network

昼夜节律基因网络整合进食时间和葡萄糖代谢

• 批准号: 9891981
• 负责人: Joseph Bass
• 金额: $ 50.11万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-15 至 2021-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891981
• 关键词: ARNTL gene; Acute; Applications Grants; Behavioral; Beta Cell; Binding; Brain; Carbohydrates; Cells; ChIP-seq; Chromatin; Circadian Dysregulation; Code; Coupling; Diabetes Mellitus; Disease; Eating; Energy Metabolism; Enhancers; Environmental Risk Factor; Epidemiology; Evaluation; Exocytosis; Fasting; Feeding Patterns; Food; Functional disorder; Funding; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomic approach; Genomics; Glucose; Goals; Grant; Growth and Development function; High Fat Diet; Homeostasis; Human; Hypothalamic structure; Impairment; Incidence; Industrialization; Insulin; Insulin Resistance; Intake; Investigation; Jet Lag Syndrome; Laboratories; Light; Link; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Molecular; Mus; Mutant Strains Mice; Mutation; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Obesity Epidemic; Overnutrition; Pacemakers; Pancreas; Pathway interactions; Periodicity; Peripheral; Phosphatidylinositols; Physiological; Physiology; Play; Post-Transcriptional Regulation; Protein Kinase C; Public Health; RNA Binding; Regulation; Research; RiboTag; Ribosomes; Risk Factors; Role; Signal Transduction; Sleep; Sleep Wake Cycle; System; Testing; Time; Tissues; Transcriptional Regulation; Translations; Variant; Work; base; blood glucose regulation; brain cell; circadian; epidemiology study; feeding; genetic approach; genome wide association study; glucose metabolism; hepatic gluconeogenesis; innovation; insight; insulin secretion; islet; molecular clock; mouse model; obesity development; obesity prevention; programs; public health relevance; response; sedentary lifestyle; shift work; transcription factor; transcriptome sequencing; vesicular release

 DESCRIPTION (provided by applicant): The escalation in the linked epidemics of obesity and diabetes mellitus has led to intensive investigation into environmental and genetic factors that contribute to the spread of these diseases. In addition to sedentary lifestyle and overnutrition, several environmental factors associated with industrialization are now believed to be linked to the development of obesity and metabolic dysfunction, including an increase in night-time shiftwork, jetlag, sleep restriction, and late-night eating, all of which can be traced to the spred of electric light. More recently, the overuse of illuminated screens that emit blue light in eReaders are also believed to induce a persistent jetlag state. While epidemiologic studies have provided mounting evidence for circadian disruption as a risk factor for metabolic disease, this work is limited as it is primarily correlative and the mechanistic basis linking circadian disorder to metabolic pathophysiology are not well established. Transformative discoveries have been that the core clock transcription factors CLOCK/BMAL1 are present not only in master pacemaker neurons of the hypothalamus, but also with within peripheral metabolic tissues, and that mutation of the mammalian Clock gene leads to obesity and metabolic syndrome, characterized by alterations in feeding time and intake, sleep, and energy expenditure. Further, during our previous grant cycle, we established that CLOCK/BMAL1 dysfunction specifically in pancreas leads to hypoinsulinemic diabetes mellitus independently of effects of the mutation on early growth and development. With analysis of the interplay between the β-cell and brain clock as the centerpiece of our grant, we have now developed inducible genetic and genomic approaches to define the molecular regulatory mechanisms through which (i) the β-cell clock controls rhythms of endogenous glucose-stimulated insulin secretion, nutrient signaling, and triggering of vesicle release through pathways involving protein kinase C and phosphoinositide, and (ii) the brain clock coordinates feeding time with activity of hypothalamic neurons regulating energy homeostasis. Our long-term objective is to test the hypothesis that circadian disruption, and the corresponding misalignment of rhythmic genomic cycles in peripheral β-cells and liver with those of brain, contributes to metabolic disorders by impairing glucose- responsive insulin secretion and desynchronizing hepatic gluconeogenesis with the sleep/wake-fasting/feeding cycle. An innovation of our work is the integration of studies of cellular and brain clock with genomic analyses to dissect the impact of clock time on glucose metabolism. Ultimately we are now poised to uncover new insight into how the central and peripheral clocks synchronize behavioral and transcriptional rhythms to impact physiology, findings which have broad implications for the treatment and prevention of obesity, metabolic syndrome, and type 2 diabetes mellitus.

 描述（由申请人提供）：肥胖和糖尿病相关流行病的升级导致了对有助于这些疾病传播的环境和遗传因素的深入研究。除了久坐不动的生活方式和营养过剩，与工业化相关的几个环境因素现在被认为与肥胖和代谢功能障碍的发展有关，包括夜间轮班的增加，时差，睡眠限制和深夜进食，所有这些都可以追溯到电灯的兴起。最近，电子书阅读器中过度使用发出蓝光的发光屏幕也被认为会引起持续的时差反应。虽然流行病学研究提供了越来越多的证据表明昼夜节律紊乱是代谢性疾病的一个危险因素，但这项工作是有限的，因为它主要是相关的，并且将昼夜节律紊乱与代谢病理生理学联系起来的机制基础还没有很好地建立。变革性的发现是，核心时钟转录因子CLOCK/BMAL 1不仅存在于下丘脑的主起搏神经元中，还存在于外周代谢组织中，并且哺乳动物时钟基因的突变导致肥胖和代谢综合征，其特征在于进食时间和摄入量，睡眠和能量消耗的改变。此外，在我们之前的资助周期中，我们确定了胰腺中的CLOCK/BMAL 1功能障碍导致低胰岛素血症糖尿病，而与突变对早期生长和发育的影响无关。通过分析β细胞和脑时钟之间的相互作用作为我们资助的核心，我们现在已经开发了诱导型遗传和基因组方法来定义分子调控机制，通过这些机制（i）β细胞时钟控制内源性葡萄糖刺激的胰岛素分泌的节律，营养信号传导，以及通过涉及蛋白激酶C和磷酸肌醇的途径触发囊泡释放，以及（ii）大脑时钟协调进食时间与调节能量稳态的下丘脑神经元的活动。我们的长期目标是检验以下假设：昼夜节律破坏以及外周β细胞和肝脏中的节律性基因组周期与大脑中的节律性基因组周期的相应不对准通过损害葡萄糖响应性胰岛素分泌和通过睡眠/清醒-禁食/进食周期使肝脏代谢异常化而促成代谢紊乱。我们工作的一个创新是将细胞和大脑时钟的研究与基因组分析相结合，以剖析时钟时间对葡萄糖代谢的影响。最终，我们现在准备揭示中枢和外周时钟如何同步行为和转录节奏以影响生理的新见解，这些发现对肥胖，代谢综合征和2型糖尿病的治疗和预防具有广泛的意义。