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我调节转录反馈环。 它协调睡眠/觉醒和生理，以预测每天太阳的升起。从流行病学来看， 临床和遗传学研究表明，生物钟失调与肥胖及其代谢协同作用有关。 病态。最近，我们已经证明了核心分子时钟组件BMAL1在 下丘脑饥饿神经元导致在昼夜循环的错误阶段增加摄食，并导致 糖耐量受损，这是糖尿病的一个标志。AgRP神经元转录组进一步识别昼夜节律 调节多巴胺能神经递质突触，表明时钟干扰可能导致 对进食的享乐式和动态平衡控制。重点是了解链接的机制 昼夜节律系统对享乐的喂养，我已经产生了新的数据来证明分子的破坏 经典奖赏促进腹侧被盖区(VTA)多巴胺能神经元的时钟导致 吞噬适口的高脂肪食物并加速饮食诱导的肥胖、高血糖、氧化损伤 呼吸测量的新陈代谢，改变了睡眠模式，减少了白天的野外行为。科学的 我目前建议的基本原理是，生物钟调节一天中不同时间的进食。 和代谢过程通过调节中脑多巴胺能区的食物相关奖赏 神经元。这项提议旨在为神经元时钟如何同步行为和 转录节律对生理学的影响，对治疗和治疗具有广泛意义的发现 预防肥胖、代谢综合征和2型糖尿病等与睡眠缺失相关的疾病。

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.