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.

项目摘要肥胖是一个主要的公共卫生问题。通过行为或药理学干预是改变能量平衡和作斗争肥胖和代谢的关键策略疾病。靶向冷诱导的非震动热发生的基础的分子途径已经是提高动物和人类能量消耗的重要策略。但是，这是很好的知道哺乳动物会补偿由于较高的支出而增加食物的摄入量，例如在寒冷中。尽管通常同意大脑在集中控制此反馈，但神经机制的基础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，代谢和冷诱导进食的电路基础。通过结合量热法和行为建模，我们的初步研究证明食物摄入的冷诱导的增加涉及动态双向行为开关并由非经典喂养电路介导。使用全脑清除，灯表成像和C-Fos 活动筛查，我们在腹部中线丘脑（VMT）上鉴定了一组核诱导的喂养。中心假设是VMT核被升高的能量激活支出和招募下游目标以介导冷引起的喂养。第一个目的是在体内使用钙成像以测量VMT与冷和进食行为关系中的内源性活性。这第二个目的是使用光遗传学和化学方法来确定VMT的因果意义驱动冷诱导喂养的神经活动。第三个目标结合了解剖图和功能性操纵研究VMT如何整合到下丘脑和边缘的公认的喂养电路中系统。这些研究的完成将为能量之间的耦合提供新的理解大脑中的支出和摄入量，带来了许多机会来利用这些机制来最大化并通过针对能源支出来维持代谢益处。