Circadian Neuronal Basis for Obesity and Diabetes

目前糖尿病和代谢综合征的公共卫生威胁仍然与糖尿病密切相关。 肥胖症在美国的流行。在病理生理学水平上，我们小组令人兴奋的研究已经在 在建立昼夜节律紊乱作为肥胖和糖尿病的一个新的危险因素的前沿。 值得注意的是，提供高脂肪饮食的动物在分子和行为上都表现出深刻的破坏， 昼夜节律、轮班工作和睡眠不足与肥胖和代谢综合征有关， 但是我们对昼夜节律紊乱与肥胖之间的相互联系机制的理解， 代谢合并症仍处于起步阶段。昼夜节律系统是由大脑按等级组织的 起搏细胞控制周围细胞的代谢周期。最近，我们的基因和基因组工作 确立了分子时钟在饥饿和外周血糖节律调节中的重要作用 通过控制NPY/AgRP神经元的稳态，揭示了对能量时钟的需求 在大脑水平上进行检测，进而将大脑生物钟病理学定位为代谢疾病的一个因素。 通过立体定向靶向，我们发现，时钟基因消融，特别是在“起搏器”神经元， 严重的肥胖，由于取消了涉及体重调节的主要区域的信号传导， 代谢和产热。这份职业发展申请的前瞻性目标是申请 生理学、遗传学和行为学的方法来确定昼夜节律的机制， 破坏有助于肥胖和糖尿病，特别关注如何破坏昼夜能量 神经元神经回路导致食欲过盛、体重增加、外周胰岛素抵抗、肝脏脂肪积累， 和骨骼肌中葡萄糖处置受损。建立在神经科学和代谢专家的基础上 该方法是利用化学遗传靶向的组合来控制 时钟能量神经元电路，从而模拟时差和睡眠中断对全身的影响 新陈代谢.分子分析将用于识别控制饥饿神经元活动的昼夜信号 和外周葡萄糖代谢，并制定行为和遗传干预措施，以减轻体重 在肥胖动物模型中。通过首先磨练上述技术，拟议的项目将使 申请人随后在临床相关模型中的R 00阶段采用这一独特的方法集 体重减轻和恢复，揭示昼夜节律中断在成功的长期减肥中的作用 并作为增加胰岛素敏感性和治疗糖尿病的干预措施。因此，这项工作具有直接 对公共卫生的转化意义，理解昼夜节律系统的慢性破坏- 由于在轮班工作，时差和夜间人工光暴露的经验-可能涉及正在进行的 肥胖症的流行总之，我们提出的研究将使申请人成为独立的 首席研究员，并将是第一个阐明机制联系昼夜节律破坏代谢 通过结合脑与外周组织研究的综合分析，

The present public health threat in diabetes mellitus and metabolic syndrome remains strongly linked to the epidemic of obesity in the US. At the pathophysiologic level, exciting studies from our group have been at the forefront in establishing circadian disruption as a novel risk factor for obesity and diabetes mellitus. Remarkably, animals provided a high-fat diet exhibit profound disruption in both molecular and behavioral circadian rhythms, and shiftwork and sleep loss has been associated with obesity and metabolic syndrome in humans, but our understanding of the mechanisms interconnecting circadian disruption with obesity and metabolic comorbidities remains in its infancy. The circadian system is organized hierarchically with brain pacemaker cells controlling metabolic cycles in peripheral cells. Recently, our genetic and genomic work has established an essential role of the molecular clock in the rhythmic regulation of hunger and peripheral glucose homeostasis through the control of NPY/AgRP neurons, revealing a requirement for the clock in energy sensing at the level of brain, and in turn, pinpointing brain clock pathologies as a factor in metabolic disease. Through stereotactic targeting, we find that clock gene ablation specifically within “pacemaker” neurons causes profound obesity, due to abrogated signaling to major regions involved in the regulation of body weight, metabolism and thermogenesis. The forward-looking goal of this career development application is to apply physiological, genetic, and behavioral approaches to determine mechanisms through which circadian disruption contributes to obesity and diabetes, with a specific focus on how disruption of circadian-energy neuron neurocircuitry leads to hyperphagia, weight gain, peripheral insulin resistance, liver fat accumulation, and impaired glucose disposal in skeletal muscle. Building on an expert neuroscientific and metabolic collaborative network the approach is to utilize a combination of chemogenetic targeting to control activity of the clock-energy neuron circuit, thereby simulating the effect of jetlag and sleep disruption on whole-body metabolism. Molecular profiling will be utilized to identify circadian signals that control hunger neuron activity and peripheral glucose metabolism, and to develop behavioral and genetic interventions to reduce body weight in animal models of obesity. By first honing the above techniques, the proposed projects will enable the applicant to subsequently employ this unique set of approaches in the R00 phase, in clinically relevant models of weight loss and regain, to uncover the role of circadian rhythm disruption in successful long-term weight loss and as an intervention to increase insulin sensitivity and treat diabetes. As such, this work has direct translational implications for public health, for understanding how chronic disruption of the circadian system – as experienced in shift work, jet lag and artificial light exposure at night – may be implicated in the ongoing obesity epidemic. In summary, our proposed research will enable the applicant to become an independent principal investigator, and will be the first to elucidate mechanisms linking circadian disruption to metabolic disease through an integrated analysis combining studies in brain with peripheral tissues.