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

基本信息

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
项目类别：
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

项目摘要

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。