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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要肥胖和代谢综合征患病率的不断上升表明，潜在的遗传和代谢综合征环境因素导致了这种流行病，我们取得了令人兴奋的发现，即基因消除。生物钟的紊乱会导致肥胖和代谢综合征，而给野生型小鼠喂食高脂肪会导致昼夜节律紊乱在不正确的昼夜节律时间（即正常休息时间）内扰乱并增加食物摄入量，即与肥胖和胰岛素抵抗直接相关，而这些观察结果表明，胰岛素抵抗具有重要作用。能量平衡中食物摄入的“时间”，潜在的中枢神经系统时钟机制我们对协调行为和代谢节律仍然知之甚少。是时钟核心分子成分的革命性发现，负转录反馈环路在视交叉上核（SCN）的起搏神经元和几乎所有的起搏神经元中循环然而，外周代谢细胞如何将额外的 SCN 时钟带入光周期， SCN 遗传上不同的细胞中的时钟在能量平衡调节中的作用仍然存在鉴于越来越多的证据表明昼夜节律和睡眠周期中断会导致代谢紊乱。通过阻碍大脑水平的信号传递，现在的主要挑战是定义起搏器的功能我们的方法是利用能量感应神经元内的神经元和时钟来建立体重设定点。是在小鼠中开发强大的新遗传模型，能够引起成年期核心消融时钟机械，并在下丘脑的特定区域内这样做，重点关注主起搏器，我们还实施了立体定向引导的 DREADD 技术（Designer Receptors Exclusively）由设计药物激活）以药理方式操纵 SCN 放电的不同阶段亚人群，从而引起遗传时差，然后探究中枢神经系统“开/关”开关的影响我们寻求整合行为、生理和分子分析。剖析 SCN 内的时钟和食欲神经元在进食和葡萄糖代谢中的作用。对人类健康有直接影响，因为我们将阐明时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总之，我们建议。研究将为起搏器神经元活动和时钟的破坏提供详细的机制见解神经基因转录的转录因子调节影响饥饿、能量的协调总之，我们提出的研究将提供详细的机制见解。 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 SCN 外区域影响饥饿、能量平衡和代谢健康的协调。