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.

概括 该研究项目的长期目标是了解控制能量平衡的机制。 最近的证据表明，脑衍生的神经营养因子（BDNF）及其TRKB受体的关键作用 在控制能量平衡中。 BDNF或TRKB基因中的突变导致小鼠和人的肥胖症 这比黑色皮质素-4受体（MC4R）突变更为严重，接近瘦素缺乏。但是，我们 关于BDNF途径的了解要少于黑素皮质素和瘦素途径 其在控制能量平衡中作用的机制。因此，通过 BDNF-TRKB途径控制体重将为肥胖发展提供新的目标 疗法。在上一届奖励期间，我们在该研究项目中取得了巨大进展。我们 已经鉴定出表达TRKB的背侧下丘脑（DMHTRKB）和室室下丘脑 （PVHTRKB）神经元作为两个食欲调节的神经元种群。我们发现trkb-的删除 这些神经元中编码NTRK2基因会导致肥胖，肥胖和化学激活 神经元极大地抑制食物摄入量。此外，我们的结果表明DMHTRKB神经元也 有力促进自适应生热。此更新应用程序将检验一个总体假设，即TRKB 信号传导通过调节与DMHTRKB互连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，我们将以三个特定目标来检验这一假设。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是确定 控制食欲的PVHTRKB神经元的靶标和输入； AIM 3是确定BDNF-TRKB信号如何 通过调节突触功能来调节食欲。这项拟议的研究将发现几个新型神经 调节食欲和/或能量消耗的电路以及奶油状态的新型机制 通过BDNF-TRKB信号传导调节食欲控制神经回路的活性。