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升级率都表明，遗传和 环境因素有助于这种流行病。我们使遗传消融的令人兴奋的发现 时钟会导致肥胖和代谢综合征，高脂喂食野生型小鼠会影响昼夜节律 在不正确的昼夜节时间（即正常休息时间）中，破坏并增加了食物摄入量 与肥胖和胰岛素抵抗直接相关。尽管这些观察结果表明 能量平衡中食物摄入的“时机”，基础的中枢神经系统时钟机制 协调行为和代谢节奏的理解仍然很差。我们学习的跳板有 是时钟的核心分子成分的变革性发现，是负转录 反馈回路是循环中的两个起搏器神经元（SCN）和几乎全部的反馈循环 外周代谢细胞。但是，大脑起搏器细胞如何进入光周期，以额外的SCN进入光周期， 时钟在SCN的遗传不同细胞中的作用在能量平衡的调节中，仍然存在 未知。鉴于昼夜节律和睡眠周期中断导致代谢障碍的越来越多的证据 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 能量感应神经元内的神经元和时钟在建立体重设定点。我们在这里的方法 是要利用小鼠中强大的新遗传模型，并能够引起成人发育的核心 时钟机械，并在下丘脑的特定区域内进行，重点关注大师起搏器， SCN。我们还实施了立体定向引导的Dreadd技术（设计器受体专门 被设计器药物激活），以在不同的不同 亚群，从而导致遗传喷射lag，然后探测中央“开/关”开关的影响 时钟的行为和能量平衡。我们试图整合行为，物理和分子分析 在喂养和葡萄糖代谢中剖析SCN和食欲神经元内时钟的作用。我们的工作 由于我们将阐明时钟系统如何减轻体重，因此已直接转化为人类健康 饮食停止后，饮食低成本的饮食和体重减轻。总而言之，我们的建议 研究将提供有关起搏器神经元活动和时钟如何破坏的详细洞察 神经元基因转录的转录因子调节会影响饥饿，能量的协调 平衡和健康。总而言之，我们拟议的研究将提供有关如何 SCN和SCN中的起搏器神经元活性和时钟调节的神经元基因转录的破坏 额外的SCN区域影响饥饿，能量平衡和代谢健康的协调。