BDNF and TrkB-containing neuronal circuits mediating energy balance

含有 BDNF 和 TrkB 的神经元回路介导能量平衡

• 批准号: 8183524
• 负责人: Maribel Rios
• 金额: $ 41.25万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8183524
• 关键词: Adult; Affect; Behavior; Body Weight; Brain; Brain-Derived Neurotrophic Factor; CD36 Antigens; Calcium; Calcium Channel; Candidate Disease Gene; Cardiovascular Diseases; Cells; Chronic; Chronic Disease; Cues; Desire for food; Development; Disease; Eating; Energy Intake; Energy Metabolism; Epidemic; Epilepsy; Equilibrium; Fasting; Funding; Gene Expression Profile; Genes; Homeostasis; Homologous Gene; Human; Hyperphagia; Hypothalamic structure; Individual; Infusion procedures; Investigation; Lasers; Lead; Ligands; Link; Mediating; Medical; Mitochondria; Molecular; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Overweight; Pathway interactions; Pharmaceutical Preparations; Play; Polypyrimidine Tract-Binding Protein; Population; Predisposition; Process; Regulation; Reporting; Rodent; Role; Satiation; Signal Pathway; Signal Transduction; Source; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic plasticity; Testing; United States; Viral; Weight Gain; disability; energy balance; feeding; gabapentin; human study; mature animal; medical complication; multidisciplinary; mutant; neural circuit; neuronal survival; neurotrophic factor; novel; obesity treatment; painful neuropathy; synaptogenesis; thrombospondin 3; treatment strategy; trend; voltage

DESCRIPTION (provided by applicant): Close to a third of the population in the United States is obese and over 60% is overweight. This is an alarming trend as obesity significantly increases susceptibility to type 2 diabetes, cardiovascular disease and other medical disorders. Mounting evidence indicates that the brain-derived neurotrophic factor (BDNF)/TrkB pathway plays a critical part in energy balance regulation and is a promising target for novel therapies. Accordingly, reduced BDNF signaling in mice and humans results in hyperphagic behavior and dramatic obesity. It remained unclear whether BDNF, which supports neuronal survival, differentiation and synaptic plasticity, acted as a required satiety factor in the adult brain or as a developmental facilitator of feeding neural circuits. As part of the previously funded project, we showed that BDNF acts in the adult animal to promote satiety and that the ventromedial hypothalamus (VMH) is a critical source of this neurotrophin. Supportive evidence includes the robust effects of energy status on expression of BDNF and TrkB in the VMH and the hyperphagia and obesity elicited by selectively deleting BDNF in the VMH of adult mice. The cellular and molecular mechanisms underlying the anorexigenic effects of BDNF in the VMH remain to be elucidated. Our recent analysis of the transcriptome of cells laser-captured from the VMH of mice with central (BDNF2L/2LCk-cre) or VMH-specific depletion of BDNF revealed decreased expression of a2d-1 and of two other genes associated with obesity susceptibility in a recent large-scale human study. Our preliminary studies show that BDNF's anorexigenic effects are mediated by a2d-1, a high voltage-gated calcium channel subunit that enhances calcium currents and mediates excitatory synaptogenesis. We found that: i) selective a2d-1 inhibition by chronic gabapentin infusion into wild type VMH increased food intake and body weight and ii) viral-mediated a2d-1 delivery to the VMH of BDNF2L/2LCk-cre mutants ameliorated their hyperphagia and body weight gain. This competitive renewal proposal seeks to build on these findings by ascertaining cellular mechanisms underlying the effects of BDNF and a2d-1. Because calcium currents in VMH cells of BDNF mutants are normal, the satiety effects of a2d-1 might be related to its ability to induce excitatory synaptogenesis in a calcium-independent manner. Thus, Aim 1 will investigate the role of BDNF and a2d-1 in dynamic changes in VMH excitatory drive onto anorexigenic POMC neurons induced by nutritional cues using anatomical and electrophysiological approaches. In Aim 2, we will investigate whether BDNF and a2d-1 also regulate excitatory drive onto anorexigenic VMH neurons. In Aim 3, we will test whether the reduced expression of two other gene candidates in the BDNF mutant VMH contributes to the emergence of hyperphagic behavior and obesity and whether they act in common pathways with a2d-1 in the VMH. These studies will provide a mechanistic understanding of anorexigenic actions of BDNF and reveal novel avenues for the treatment of obesity. PUBLIC HEALTH RELEVANCE: Obesity is a pervasive disorder linked to serious medical complications and reaching epidemic proportions in the United States. New and efficacious treatment strategies are urgently needed. Dysregulation of brain- derived neurotrophic factor (BDNF) signaling in the brain contributes to excessive eating and body weight gain but the underlying disease mechanisms are poorly understood. We will examine candidate cellular and molecular mechanisms that might drive increases in food intake in individuals with deficient levels of BDNF. These investigations will facilitate the creation of new avenues for the treatment of obesity.

描述（由申请人提供）：美国近三分之一的人口肥胖，超过 60% 的人超重。这是一个令人震惊的趋势，因为肥胖会显着增加对 2 型糖尿病、心血管疾病和其他疾病的易感性。越来越多的证据表明，脑源性神经营养因子 (BDNF)/TrkB 通路在能量平衡调节中发挥着关键作用，是新疗法的一个有希望的靶点。因此，小鼠和人类的 BDNF 信号传导减少会导致贪食行为和严重肥胖。目前尚不清楚支持神经元存活、分化和突触可塑性的 BDNF 是否充当成人大脑所需的饱腹感因子或作为喂养神经回路的发育促进剂。作为先前资助项目的一部分，我们表明 BDNF 在成年动物中发挥作用以促进饱腹感，并且下丘脑腹内侧 (VMH) 是这种神经营养素的重要来源。支持性证据包括能量状态对 VMH 中 BDNF 和 TrkB 表达的强烈影响，以及通过选择性删除成年小鼠 VMH 中的 BDNF 引起的食欲亢进和肥胖。 BDNF 在 VMH 中产生厌食作用的细胞和分子机制仍有待阐明。我们最近对从具有中枢 (BDNF2L/2LCk-cre) 或 VMH 特异性 BDNF 缺失的小鼠 VMH 中激光捕获的细胞转录组进行分析，发现 a2d-1 和其他两个与肥胖易感性相关的基因的表达降低。最近的大规模人体研究。我们的初步研究表明，BDNF 的厌食作用是由 a2d-1 介导的，a2d-1 是一种高压门控钙通道亚基，可增强钙电流并介导兴奋性突触发生。我们发现：i) 通过长期向野生型 VMH 输注加巴喷丁选择性抑制 a2d-1，增加了食物摄入量和体重；ii) 病毒介导的 a2d-1 递送至 BDNF2L/2LCk-cre 突变体的 VMH，改善了其食欲亢进和身体状况体重增加。这项竞争性更新提案旨在通过确定 BDNF 和 a2d-1 作用的细胞机制来建立在这些发现的基础上。由于 BDNF 突变体的 VMH 细胞中的钙电流是正常的，a2d-1 的饱腹感作用可能与其以不依赖钙的方式诱导兴奋性突触发生的能力有关。因此，目标 1 将使用解剖学和电生理学方法研究 BDNF 和 a2d-1 在 VMH 兴奋性驱动对营养线索诱导的厌食 POMC 神经元动态变化中的作用。在目标 2 中，我们将研究 BDNF 和 a2d-1 是否也调节厌食 VMH 神经元的兴奋性驱动。在目标 3 中，我们将测试 BDNF 突变体 VMH 中另外两个候选基因表达的减少是否会导致贪食行为和肥胖的出现，以及它们是否与 VMH 中的 a2d-1 共同发挥作用。这些研究将为 BDNF 的厌食作用提供机制理解，并揭示治疗肥胖的新途径。 公共卫生相关性：肥胖是一种普遍存在的疾病，与严重的医疗并发症有关，在美国已达到流行病的程度。迫切需要新的有效的治疗策略。大脑中脑源性神经营养因子（BDNF）信号的失调会导致过度饮食和体重增加，但人们对潜在的疾病机制知之甚少。我们将研究可能导致 BDNF 水平不足的个体食物摄入量增加的候选细胞和分子机制。这些研究将有助于创造治疗肥胖的新途径。