MCHergic control of feeding and energy balance in the LH area

MCHergic 控制 LH 区域的摄食和能量平衡

• 批准号: 10649474
• 负责人: XIAO-BING GAO
• 金额: $ 42.49万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10649474
• 关键词: Ablation; Address; Animals; Anorexia; Area; Arousal; Behavioral; Body Weight; Body fat; Brain; Cells; Consumption; Country; Data; Development; Disease; Disease Management; Eating; Economics; Energy Intake; Energy Metabolism; Equilibrium; Fasting; Feedback; Feeding behaviors; Food; Genetic; Glutamates; Goals; Health; Homeostasis; Human; Hunger; Hyperactivity; Hypothalamic structure; Impairment; In Vitro; Investigation; Knowledge; Lateral; Long-Term Potentiation; MCHR1 gene; Mediating; Metabolic; Modification; Molecular; Morphology; Motivation; Mus; Neuronal Plasticity; Neurons; Neuropeptides; Neurotransmitters; Obesity; Organism; Pathway interactions; Persons; Phenotype; Play; Process; Regulation; Reporting; Role; Signal Transduction; Slice; Synapses; Synaptic plasticity; System; Testing; Thinness; Translating; United States; Vesicle; antagonist; design; designer receptors exclusively activated by designer drugs; diet-induced obesity; energy balance; experimental study; feeding; food environment; hypocretin; in vivo; mature animal; melanin-concentrating hormone; mouse model; nerve supply; preservation; promoter; receptor; response; synaptic function

Obesity, referring to having an abnormally high proportion of body fat, has become a health and economic problem in wealthy countries such as the United States. Therefore, intensive investigations have been conducted to determine the factors leading to the positive energy balance between energy intake and energy expenditure. The hypothalamus plays a substantial role in the regulation of energy intake and expenditure. However, it is still not clear how various neuronal systems in the hypothalamus interact to maintain normal body weight and how the dys-regulated interactions may compromise the balance between energy intake and expenditure. In this application we propose to identify interactions between melanin-concentrating hormone- synthesizing (MCH) neurons and hypocretin (Hcrt) neurons in the lateral hypothalamus in the regulation of energy balance and body weight at molecular, cellular and whole animal levels. Both MCH and Hcrt systems are critical players in the regulation of energy balance in animals and humans. The MCH system promotes energy intake and decreases energy expenditure while the Hcrt system promotes both energy intake and expenditure. There has been morphological and functional evidence on the possible interactions between these two systems. However, it is still not entirely clear whether the interaction between these two systems is required in the regulation of energy balance in animals and humans and whether changes in the interaction may lead to altered responses of the brain to the energy status of organisms and compromised energy metabolism. Based on current data we hypothesize that a crosstalk between MCH and Hcrt systems is required to maintain normal body weight. Specifically, we propose that the MCH system requires activation from Hcrt cells to promote energy intake, while MCH neurons may provide a feedback pathway to limit the activity in the Hcrt system to curb energy expenditure and maintain the normal body weight in animals. Since neuronal plasticity plays a critical role in the formation and modification of homeostatic and behavioral functions in animals, it is very likely that the modulation of synaptic function in MCH and Hcrt neurons could be one of the mechanisms underlying the interaction between these two systems. Therefore, three goals of this application are: 1) To test the hypothesis that MCH-mediated food intake requires activation from the Hcrt system in animals.; 2) To interrogate the hypothesis that the MCH system is required to limit activity in the Hcrt system to curb energy expenditure; and 3) To examine whether the imbalance between the activities in MCH and Hcrt cells underlie dys-regulated metabolic status (DIO and anorexia) in animals. The answers to these questions will help address the crosstalk between homeostatic centers in the hypothalamus and the role of the crosstalk in the determination of energy metabolism. We hope that this project will benefit people suffering from diseases/conditions (such as obesity and anorexia) resulting from impaired regulation of energy metabolism.

肥胖是指体内脂肪比例异常高，已成为一种健康和经济问题 美国等富裕国家的问题。因此，经过深入调查 确定导致能量摄入和能量之间正能量平衡的因素 支出。下丘脑在能量摄入和消耗的调节中起着重要作用。 然而，目前尚不清楚下丘脑的各个神经元系统如何相互作用以维持正常 体重以及失调的相互作用如何损害能量摄入和体重之间的平衡 支出。在此应用中，我们建议确定黑色素浓缩激素之间的相互作用 下丘脑外侧的合成（MCH）神经元和下丘脑（Hcrt）神经元在调节 分子、细胞和整个动物水平的能量平衡和体重。 MCH 和 Hcrt 系统 是调节动物和人类能量平衡的关键参与者。妇幼卫生系统促进 能量摄入并减少能量消耗，而 Hcrt 系统则促进能量摄入和能量消耗 支出。形态学和功能证据表明两者之间可能存在相互作用 这两个系统。然而，目前尚不完全清楚这两个系统之间的相互作用是否有效。 动物和人类能量平衡调节所必需的，以及相互作用是否发生变化 可能导致大脑对生物体能量状态的反应改变和能量受损 代谢。根据当前数据，我们假设 MCH 和 Hcrt 系统之间的串扰是 维持正常体重所需。具体来说，我们建议MCH系统需要激活 Hcrt 细胞促进能量摄入，而 MCH 神经元可能提供反馈途径来限制 Hcrt 系统中的活性可抑制动物的能量消耗并维持正常体重。自从 神经元可塑性在稳态和行为的形成和改变中起着至关重要的作用 动物中的功能，MCH 和 Hcrt 神经元突触功能的调节很可能是 这两个系统之间相互作用的机制之一。因此，本次活动的三个目标 应用包括： 1) 检验 MCH 介导的食物摄入需要 Hcrt 激活的假设 动物体内的系统。 2) 质疑 MCH 系统需要限制 Hcrt 活动的假设 控制能源支出的制度； 3) 检查妇幼保健活动之间是否存在不平衡 Hcrt 细胞是动物代谢失调（DIO 和厌食）的基础。这些问题的答案 问题将有助于解决下丘脑稳态中心之间的串扰以及 能量代谢测定中的串扰。希望这个项目能够造福于患有此病的人们 由于能量代谢调节受损而导致的疾病/病症（例如肥胖和厌食症）。