Neural Mechanisms of Energy Expenditure-Induced Compensatory Food Intake

能量消耗引起的补偿性食物摄入的神经机制

• 批准号: 10735758
• 负责人: Li Ye
• 金额: $ 71.75万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-20 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735758
• 关键词: Acute; Affect; Agreement; Anatomy; Animals; Automobile Driving; Behavior; Behavioral; Behavioral Model; Biological Assay; Body Temperature; Brain; Calorimetry; Cell Nucleus; Collaborations; Compensation; Costs and Benefits; Couples; Coupling; Data; Eating; Energy Intake; Energy Metabolism; Esthesia; Etiology; Exercise; Expenditure; FOS gene; Fasting; Fatty acid glycerol esters; Feedback; Feeding behaviors; Fiber; Food; Foundations; Future; Genetic; Goals; Homeostasis; Human; Hypothalamic structure; Image; Intervention; Light; Limbic System; Mammals; Maps; Measures; Mediating; Metabolic; Metabolic Diseases; Metabolism; Midline Thalamic Nuclei; Modeling; Molecular Target; Natural Increases; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Output; Pathway interactions; Photometry; Physiological; Public Health; Regulation; Research; Rewards; Rodent; Role; Signal Transduction; System; Techniques; Thalamic structure; Thermogenesis; energy balance; feeding; gain of function; genetic approach; in vivo; in vivo calcium imaging; insight; loss of function; neural; neuromechanism; optogenetics; pharmacologic; recruit; screening

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.

项目概要 肥胖是一个重大的公共卫生问题。通过行为或调节能量消耗 药物干预是改变能量平衡、对抗肥胖和代谢的关键策略 疾病。针对寒冷诱导的非颤抖生热作用的分子途径已被研究 这是提高动物和人类能量消耗的重要且有前途的策略。不过，也还好—— 众所周知，哺乳动物会由于较高的支出（例如在寒冷中）而补偿性地增加食物摄入量。 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、代谢和 冷诱导喂养的电路基础。通过结合量热法和行为建模，我们的初步研究 证明寒冷引起的食物摄入量增加涉及动态双向行为转换 并由非规范喂养电路介导。使用全脑清除、光片成像和 c-fos 通过活动筛选，我们在丘脑腹侧中线 (vMT) 确定了一组与冷相关的核团 诱导喂养。中心假设是 vMT 核被高能量激活 支出并招募下游目标来调解寒冷诱导的喂养。第一个目标是在体内使用 钙成像测量 vMT 与寒冷和进食行为相关的内源性活性。这 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 驱动冷诱导进食的神经活动。第三个目标结合了解剖图和功能 操作来研究 vMT 如何整合到下丘脑和边缘系统中完善的喂养回路中 系统。这些研究的完成将为能源之间的耦合提供新的认识。 大脑的支出和摄入，带来了许多机会利用这些机制来最大化 并保持以能量消耗为目标的代谢益处。