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，指的是身体脂肪比例异常高，已经成为一种健康和经济的 这是美国等富裕国家的问题。因此，密集的调查一直在进行 确定导致能量摄入量和能量正向平衡的因素 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，目前仍不清楚下丘脑中的各种神经系统如何相互作用以维持正常 体重以及Dys调节的相互作用可能如何破坏能量摄入和 支出。在这项应用中，我们建议确定黑色素浓缩激素- 下丘脑外侧区合成(MCH)神经元和下丘脑下丘脑下丘脑下丘脑(Hcrt)神经元的调节 在分子、细胞和整个动物水平上的能量平衡和体重。妇幼保健院和HCRT系统 在调节动物和人类的能量平衡方面起着关键作用。妇幼保健制推广 能量摄取和减少能量消耗，而高速铁路系统促进能量摄入量和 支出。已经有形态和功能上的证据表明， 这两个系统。然而，目前仍不完全清楚这两个系统之间的互动是否 在调节动物和人类的能量平衡中所需要的，以及在相互作用中是否发生变化 可能导致大脑对生物体的能量状态和能量受损的反应改变 新陈代谢。根据目前的数据，我们假设妇幼保健器和HCRT系统之间的串扰是 维持正常体重所必需的。具体地说，我们建议妇幼保健系统需要激活 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系统中抑制能量消耗和维持动物正常体重的活动。自.以来 神经元可塑性在动态平衡和行为学的形成和改变中起着关键作用 在动物中的功能，很可能是MCH和Hcrt神经元中突触功能的调节 这两个系统之间相互作用的基础机制之一。因此，这其中的三个目标 其应用是：1)检验MCH介导的食物摄取需要从HCRT激活的假设 动物中的系统；2)询问关于妇幼保健系统需要限制HCRT中的活动的假设 控制能源消耗的制度；以及3)审查妇幼保健活动之间的不平衡 而Hcrt细胞是动物动态调节代谢状态(DIO和厌食症)的基础。这些问题的答案是 这些问题将有助于解决下丘脑内平衡中心之间的串扰问题，以及 串扰在测定能量代谢中的作用。我们希望这个项目将造福于遭受 由于能量代谢调节受损而导致的疾病/状况(如肥胖和厌食症)。