TrkB neurons in the control of body weight

TrkB 神经元控制体重

• 批准号: 10393592
• 负责人: BAOJI XU
• 金额: $ 60.09万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393592
• 关键词: Action Potentials; Address; Adolescent obesity; Adult; Appetite Regulation; Area; Award; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Cardiovascular Diseases; Data; Desire for food; Eating; Electrophysiology (science); Emotions; Energy Metabolism; Fasting; Genes; Goals; Human; Hyperphagia; Hypothalamic structure; In Situ Hybridization; Lateral; Lead; Leptin; Leptin deficiency; Life; Light; Malignant Neoplasms; Maps; Mediating; Melanocortin 4 receptor mutation; Metabolic Diseases; Mus; Mutation; NTRK2 gene; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Physical activity; Population; Preoptic Areas; Property; Publishing; Research; Research Project Grants; Risk; Role; Signal Transduction; Source; Structure of nucleus infundibularis hypothalami; Testing; Therapeutic; Therapeutic Intervention; Thermogenesis; Time; United States; Virus; base; circadian regulation; energy balance; experimental study; feeding; neural circuit; new therapeutic target; novel; obesity development; parabrachial nucleus; postsynaptic; synaptic function

Summary The long-term goal of this research project is to understand the mechanism by which energy balance is regulated. Recent evidence has shown a critical role for brain-derived neurotrophic factor (BDNF) and its TrkB receptor in the control of energy balance. Mutations in the gene for BDNF or TrkB lead to obesity in both mice and humans that is more severe than melanocortin-4 receptor (MC4R) mutations and close to leptin deficiency. However, we know much less about the BDNF pathway than the melanocortin and leptin pathways with regard to the mechanisms underlying their roles in the control of energy balance. Therefore, elucidation of the mechanism by which the BDNF-TrkB pathway controls body weight will provide novel targets for development of obesity therapeutics. We have made tremendous progress in this research project during the prior award period. We have identified TrkB-expressing dorsomedial hypothalamus (DMHTrkB) and paraventricular hypothalamus (PVHTrkB) neurons as two appetite-regulating neuronal populations. We have found that deletion of the TrkB- encoding Ntrk2 gene in these neurons leads to hyperphagia and obesity and chemogenetic activation of these neurons dramatically suppresses food intake. Furthermore, our results indicate that DMHTrkB neurons also potently promote adaptive thermogenesis. This renewal application will test an overarching hypothesis that TrkB signaling controls energy balance by modulating synaptic function of neural circuits interconnecting with DMHTrkB and PVHTrkB neurons. More specifically, we will test this hypothesis in three specific aims. Aim 1 is to identify neural circuits through which DMHTrkB neurons regulate energy expenditure and appetite; Aim 2 is to Identify the targets and inputs of PVHTrkB neurons that control appetite; Aim 3 is to determine how BDNF-TrkB signaling regulates appetite by modulating synaptic function. This proposed research will uncover several novel neural circuits that regulate appetite and/or energy expenditure as well as novel mechanisms by which prandial state modulates the activity of appetite-controlling neural circuits through BDNF-TrkB signaling.

摘要 这项研究项目的长期目标是了解能量平衡的调节机制。 最近的证据表明脑源性神经营养因子(BDNF)及其TrkB受体具有重要作用 在控制能量平衡方面。BDNF或TrkB基因突变导致小鼠和人类肥胖 这比黑素皮质素-4受体(MC4R)突变更严重，接近瘦素缺乏症。然而，我们 与黑素皮质素和瘦素途径相比，对BDNF途径的了解要少得多 它们在控制能量平衡中的作用的潜在机制。因此，通过以下方式阐明这一机制 BDNF-TrkB途径控制体重将为肥胖的发展提供新的靶点 治疗学。在之前的获奖期间，我们在这项研究项目上取得了巨大的进展。我们 已发现表达TrkB的下丘脑背内侧(DMHTrkB)和下丘脑室旁 (PVHTrkB)神经元是两类食欲调节神经元。我们发现TrkB的删除- 在这些神经元中编码NTRK2基因会导致过度吞噬和肥胖，并导致这些细胞的化学激活 神经元会戏剧性地抑制食物的摄入。此外，我们的结果表明，DMHTrkB神经元也 有力地促进适应性产热。此续订申请将测试TrkB的总体假设 信号通过调节与DMHTrkB相互连接的神经回路的突触功能来控制能量平衡 和PVHTrkB神经元。更具体地说，我们将在三个具体目标上检验这一假设。目标1是确定 DMHTrkB神经元调节能量消耗和食欲的神经回路；目标2是识别 控制食欲的PVHTrkB神经元的靶点和输入；目标3是确定BDNF-TrkB信号如何 通过调节突触功能来调节食欲。这项拟议的研究将揭示几个新的神经 调节食欲和/或能量消耗的回路以及饮食状态的新机制 通过BDNF-TrkB信号调节食欲控制神经回路的活动。