The Circadian System as a Neuronal Regulator of Feeding Time and Body Weight Setpoint

昼夜节律系统作为喂养时间和体重设定值的神经调节器

• 批准号: 10220955
• 负责人: Joseph Bass
• 金额: $ 42.78万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220955
• 关键词: ARNTL gene; Ablation; Adult; Behavior; Behavioral; Body Weight; Body Weight decreased; Brain; Caloric Restriction; Cells; Circadian Dysregulation; Consumption; Desire for food; Diet; Dissection; Eating; Energy Metabolism; Environmental Risk Factor; Epidemic; Epidemiology; Failure; Fatty acid glycerol esters; Feedback; Food; Genes; Genetic; Genetic Models; Genetic Transcription; Health; Hepatic; High Fat Diet; Homeostasis; Human; Hunger; Hypothalamic structure; Individual; Insulin Resistance; Intervention; Jet Lag Syndrome; Knowledge; Lead; Leptin; Light; Link; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Molecular; Molecular Analysis; Mus; Mutant Strains Mice; Narcolepsy; Neuraxis; Neurons; Obesity; Pacemakers; Periodicity; Peripheral; Pharmacology; Phase; Physiological; Play; Prevalence; Process; Regulation; Research; Resistance; Rest; Role; Series; Signal Transduction; Sleep; Sleep Wake Cycle; Structure of nucleus infundibularis hypothalami; Syndrome; System; Technology; Testing; Thermogenesis; Time; Vasoactive Intestinal Peptide; Weight; Wild Type Mouse; Work; blood glucose regulation; cell type; circadian; circadian pacemaker; circadian regulation; combat; designer receptors exclusively activated by designer drugs; diet-induced obesity; dieting; energy balance; experimental study; feeding; food consumption; genetic manipulation; glucose metabolism; glucose production; improved; insight; molecular clock; nodal myocyte; obese person; obesity development; response; shift work; suprachiasmatic nucleus; transcription factor; translation to humans; weight maintenance

Project Summary The escalating prevalence of obesity and metabolic syndrome suggest that both underlying genetic and environmental factors contribute to this epidemic. We have made the exciting discoveries that genetic ablation of the clock leads to obesity and metabolic syndrome, and high-fat feeding to wild-type mice induces circadian disruption and increases food intake during the incorrect circadian time (i.e., their normal rest period) that is directly linked to obesity and insulin resistance. While these observations suggest a fundamental role for the “timing” of food intake in energy balance, the underlying central nervous system clock mechanisms coordinating behavioral and metabolic rhythms remain poorly understood. A springboard for our studies has been the transformative discovery of the core molecular components of the clock, a negative transcription feedback loop that cycles in both pacemaker neurons of the suprachiasmatic nucleus (SCN) and nearly all peripheral metabolic cells. However, how the brain pacemaker cells entrain extra-SCN clocks to the light cycle, and the role of clocks within genetically distinct cells of the SCN in the regulation of energy balance, remains unknown. Given the mounting evidence that circadian and sleep cycle disruption lead to metabolic disorders through impeding signaling at the level of brain, a primary challenge is now to define the function of pacemaker neurons and clocks within energy-sensing neurons in establishing body weight setpoint. Our approach herein is to exploit powerful new genetic models in the mouse, with the ability to cause adult-onset ablation of the core clock machinery, and to do so within specific region of the hypothalamus, focusing on the master pacemaker, the SCN. We also implement stereotactically-guided DREADD technology (Designer Receptors Exclusively Activated by Designer Drugs) to pharmacologically manipulate the phase of SCN firing in distinct subpopulations, thus causing genetic jetlag, and to then probe the impact of this “on/off” switch of the central clock on behavior and energy balance. We seek to integrate behavioral, physiological, and molecular analyses to dissect actions of the clock within SCN and appetitive neurons in feeding and glucose metabolism. Our work has direct translation to human health since we will elucidate how the clock system contributes to weight loss with hypocaloric diets and maintenance of weight loss following cessation of dieting. In summary, our proposed research will provide detailed mechanistic insight into how disruption of pacemaker neuron activity and clock transcription factor regulation of neuronal gene transcription impacts the coordination of hunger, energy balance, and health. In summary, our proposed research will provide detailed mechanistic insight into how disruption of pacemaker neuron activity and clock-regulated neuronal gene transcription in both SCN and extra-SCN regions impact the coordination of hunger, energy balance and metabolic health.

项目摘要 肥胖和代谢综合征的发病率不断上升，这表明潜在的遗传和 环境因素助长了这一流行病。我们有了令人兴奋的发现， 导致肥胖和代谢综合征，高脂肪喂养野生型小鼠诱导昼夜节律 中断并在不正确的昼夜节律时间期间增加食物摄入（即，正常的休息时间）， 与肥胖和胰岛素抵抗直接相关。虽然这些观察表明， “定时”食物摄入的能量平衡，潜在的中枢神经系统时钟机制 协调行为和代谢节律仍然知之甚少。我们学习的跳板 是时钟的核心分子组成部分的变革性发现，负转录 反馈回路，在视交叉上核（SCN）的起搏神经元和几乎所有 外周代谢细胞然而，大脑起搏细胞如何将额外的SCN时钟带入光周期， 以及SCN的遗传上不同的细胞内的时钟在调节能量平衡中的作用， 未知鉴于越来越多的证据表明昼夜节律和睡眠周期紊乱会导致代谢紊乱 通过阻碍大脑水平的信号传导，现在的主要挑战是定义起搏器的功能。 在建立体重设定点中，能量感测神经元内的神经元和时钟。我们的方法 是在小鼠中开发强大的新遗传模型，具有引起成年发作的核心消融的能力， 时钟机械，并在下丘脑的特定区域内这样做，专注于主起搏器， 的SCN。我们还实施立体定向引导的DREADD技术（设计师专用接收器 由设计药物激活），以在不同的时间段内操纵SCN放电的相位。 亚群，从而造成遗传时差，然后探索这种“开/关”开关的影响，中央 时钟的行为和能量平衡。我们寻求整合行为、生理和分子分析 剖析SCN内的生物钟和食欲神经元在摄食和葡萄糖代谢中的作用。我们的工作 因为我们将阐明生物钟系统如何有助于减肥， 低热量饮食和停止节食后维持体重减轻。综上所述，我们的建议 研究将提供详细的机制洞察如何破坏起搏神经元的活动和时钟 神经元基因转录的转录因子调节影响饥饿、能量和神经元之间的协调。 平衡和健康。总之，我们提出的研究将提供详细的机制洞察如何 SCN和SCN中起搏神经元活动和时钟调节神经元基因转录的破坏 超SCN区域影响饥饿、能量平衡和代谢健康的协调。