Circadian Mechanisms of Hedonic Feeding in Obesity

项目摘要 生物钟是存在于大脑和外周组织中的自动调节转录反馈环 它协调睡眠/觉醒和生理，以期待每天的太阳升起。流行病学， 临床和遗传学研究表明，生物钟失调导致肥胖及其代谢协同作用， 病态最近，我们已经表明，废除的核心分子时钟组件BMAL 1在 下丘脑饥饿神经元导致在日/夜周期的错误阶段增加进食， 葡萄糖耐量受损是糖尿病的标志AgRP神经元转录组学进一步确定昼夜节律 多巴胺能神经递质突触的调节，表明生物钟中断可能导致多巴胺能神经递质突触的改变。 对进食的享乐和自我平衡的控制。重点是了解 昼夜节律系统享乐喂养，我已经产生了新的数据表明，破坏的分子 经典的奖励促进腹侧被盖区（VTA）多巴胺能神经元的生物钟导致 食欲过盛的可口的高脂肪食物，并加速饮食引起的肥胖，高血糖症，受损的氧化 通过呼吸测定法测定代谢，改变睡眠模式，并减少白天的露天行为。科学 我现在提出的基本原理是生物钟调节一天中的进食时间 和代谢过程通过调节食物相关的奖励在中脑多巴胺能 神经元该提案旨在为神经元时钟如何同步行为和行为提供新的见解。 转录节律影响生理学，这些发现对治疗和 预防与肥胖、代谢综合征和2型糖尿病有关的睡眠丧失疾病。

Project Summary The circadian clock is an auto-regulatory transcription feedback loop present in the brain and peripheral tissues that coordinates sleep/wake and physiology in anticipation of the rising of the sun each day. Epidemiologic, clinical and genetic studies have shown clock dysregulation contributes to both obesity and its metabolic co- morbidities. Recently, we have shown that abrogation of the core molecular clock component BMAL1 in hypothalamic hunger neurons leads to increased feeding at the wrong phase of the day/night cycle and causes impaired glucose tolerance, a hallmark of diabetes. AgRP neuron transcriptomics further identify circadian regulation of dopaminergic neurotransmitter synapse, indicating that clock disruption may lead to alterations in both the hedonic and homeostatic control of feeding. With a focus on understanding the mechanisms linking circadian systems to hedonic feeding, I have generated new data demonstrating that disruption of the molecular clock in dopaminergic neurons of the classical reward-promoting ventral tegmental area (VTA) results in hyperphagia of palatable high fat food and accelerates diet-induced obesity, hyperglycemia, impaired oxidative metabolism by respirometry, altered sleep patterns, and decreased daytime open field behavior. The scientific rationale underlying my present proposal is that the circadian clock modulates time-of-day dependent feeding and metabolic processes through the regulation of food-associated reward within midbrain dopaminergic neurons. This proposal seeks to contribute new insight into how neuronal clocks synchronize behavioral and transcriptional rhythms to impact physiology, findings which have broad implications for the treatment and prevention of sleep-loss related disorders of obesity, metabolic syndrome, and type 2 diabetes mellitus.