Neural Mechanisms of Energy Expenditure-Induced Compensatory Food Intake

项目摘要 肥胖是一个主要的公共卫生问题。调节能量消耗通过行为或 药物干预是改变能量平衡、对抗肥胖和代谢紊乱的关键策略。 疾病针对冷诱导的非颤抖性产热的分子途径已经被 这是一个重要的和有前途的策略，以提高动物和人类的能量消耗。但是，这是很好的- 已知哺乳动物补偿性地增加食物摄入是由于较高的消耗，例如在寒冷中。 虽然人们普遍认为大脑集中控制这种反馈，但其背后的神经机制 这种耦合在很大程度上是未知的。在这里，我们建议系统地研究行为，代谢， 冷诱导馈电的电路基础。通过结合量热法和行为建模，我们的初步研究 表明，冷诱导的食物摄入量增加涉及动态的双向行为开关， 并且由非规范馈电电路介导。利用全脑清除光片成像和c-fos 活动筛选，我们确定了一组核腹中线丘脑（vMT）与冷- 诱导喂养中心假设是vMT核被升高的能量激活 支出和招募下游目标来调解冷诱导的摄食。第一个目标是在体内使用 钙成像，以测量与寒冷和进食行为相关的vMT的内源性活性。的 第二个目标是使用光遗传学和化学遗传学方法来确定vMT的因果意义 在驱动冷诱导进食中的神经活动。第三个目标结合解剖映射和功能 操作，以研究vMT如何整合到下丘脑和边缘系统中已建立的进食回路中 系统.这些研究的完成将对能量之间的耦合提供新的认识 大脑中的消耗和摄入，带来了许多机会来利用这些机制，以最大限度地提高 并保持目标能量消耗的代谢益处。

Project Summary Obesity is a major public health problem. Modulating energy expenditure through behavioral or pharmacological intervention is a key strategy to alter energy balance and battle obesity and metabolic diseases. Targeting molecular pathways underlying the cold-induced non-shivering thermogenesis has been an important and promising strategy to elevate energy expenditure in animals and humans. However, it is well- known that mammals compensatorily increase food intake due to higher expenditure, such as in the cold. While it is generally agreed that the brain centrally controls this feedback, the neural mechanism underlying this coupling is largely unknown. Here, we propose to systematically investigate the behavioral, metabolic, and circuit basis of cold-induced feeding. By combining calorimetry and behavioral modeling, our preliminary study demonstrated that cold-induced increase of food intake involves dynamic bi-directional behavioral switches and is mediated by non-canonical feeding circuits. Using whole-brain clearing, lightsheet imaging, and c-fos activity screening, we identified a group of nuclei at the ventral midline thalamus (vMT) associated with cold- induced feeding. The central hypothesis is that the vMT nuclei are activated by the elevated energy expenditure and recruit downstream targets to mediate cold-induced feeding. The first aim is to use in vivo calcium imaging to measure the endogenous activity of vMT in relationship to cold and feeding behaviors. The second aim is to use optogenetic and chemogenetic approaches to determine the causal significance of vMT neural activity in driving cold-induced feeding. The third aim combines anatomical mapping and functional manipulation to study how vMT integrates into the well-established feeding circuits in hypothalamic and limbic systems. The completion of these studies will provide a new understanding of the coupling between energy expenditure and intake in the brain, bringing many opportunities to leverage these mechanisms to maximize and maintain the metabolic benefits from targeting energy expenditure.