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

项目摘要 肥胖和代谢综合征患病率的不断上升表明，潜在的遗传和 环境因素导致了这种流行病。我们已经有了令人兴奋的发现，基因消融 时钟的变化会导致肥胖和代谢综合症，而给野生型小鼠喂食高脂肪会导致昼夜节律 干扰并在不正确的昼夜节律时间(即正常休息时间)增加食物摄入量 与肥胖和胰岛素抵抗直接相关。虽然这些观察结果表明， 能量平衡中食物摄取的“时机”，这是中枢神经系统潜在的时钟机制 协调的行为和代谢节律仍然知之甚少。我们学习的跳板是 被变革性地发现了时钟的核心分子成分，负转录 在视交叉上核(SCN)的两个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， 而SCN中遗传上不同的细胞内的时钟在调节能量平衡方面的作用仍然存在。 未知。鉴于越来越多的证据表明昼夜节律和睡眠周期的紊乱会导致代谢紊乱 通过在大脑水平上阻碍信号传递，现在的一个主要挑战是定义起搏器的功能 能量感受型神经元和时钟在建立体重设定点中的作用。我们在这里的方法 是在小鼠身上开发出强大的新遗传模型，具有导致成人期核心消融的能力 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， SCN。我们还实施了立体引导的DREADD技术(Designer Receiver独家 由特制药物激活)，以药理方式操纵SCN在不同的 亚群，从而造成遗传时差，然后探索这种“开/关”的影响中央 在行为和能量平衡上计时。我们试图将行为、生理和分子分析结合起来 解剖SCN内的时钟和食欲神经元在摄食和糖代谢中的作用。我们的工作 对人类健康有直接的影响，因为我们将阐明时钟系统如何有助于减肥 低卡路里饮食和在停止节食后保持减肥。总而言之，我们的建议 研究将提供详细的机制洞察如何扰乱起搏器神经元的活动和时钟 转录因子对神经元基因转录的调控影响饥饿、能量的协调 平衡和健康。总而言之，我们提议的研究将提供详细的机械性洞察 SCN和SCN中起搏神经元活性和时钟调节神经元基因转录的中断 SCN外区域影响饥饿、能量平衡和新陈代谢健康的协调。

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.