TrkB neurons in the control of body weight

总结 该研究项目的长期目标是了解调节能量平衡的机制。 最近的证据表明，脑源性神经营养因子（BDNF）及其TrkB受体的关键作用 控制能量平衡。BDNF或TrkB基因突变导致小鼠和人类肥胖 这比黑皮质素-4受体（MC 4 R）突变更严重，接近瘦素缺乏症。但我们 对于BDNF通路的了解比黑皮质素和瘦素通路少得多， 它们在控制能量平衡中的作用机制。因此，通过以下方式阐明该机制： BDNF-TrkB通路控制体重将为肥胖的发展提供新的靶点 治疗学我们在上一个获奖期间在这个研究项目上取得了巨大的进展。我们 已经鉴定了表达TrkB的背内侧下丘脑（DMHTrkB）和室旁下丘脑 （PVHTrkB）神经元作为两个食欲调节神经元群体。我们发现TrkB的缺失- 这些神经元中编码Ntrk 2基因的基因导致这些神经元的过度吞噬和肥胖以及化学发生激活。 神经元显著抑制食物摄入。此外，我们的研究结果表明，DMHTrkB神经元也 有效地促进适应性产热。此更新申请将测试TrkB的总体假设 信号通过调节与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，我们将在三个具体目标中检验这一假设。目标1：识别 DMHTrkB神经元调节能量消耗和食欲的神经回路;目的2是确定DMHTrkB神经元的功能。 控制食欲的PVHTrkB神经元的靶点和输入;目的3是确定BDNF-TrkB信号传导如何 通过调节突触功能来调节食欲。这项拟议中的研究将揭示几种新的神经 调节食欲和/或能量消耗的回路以及膳食状态 通过BDNF-TrkB信号调节食欲控制神经回路的活动。

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.