Regulation of food intake and body weight by dendritically synthesized BDNF

描述(申请人提供)：脑源性神经营养因子(BDNF)及其TrkB受体在人类和小鼠的能量平衡控制中都有牵连。以往的研究表明，下丘脑腹内侧核(VMH)表达的BDNF在调节能量平衡中起着重要作用。BDNF蛋白在神经元胞体和树突中合成。在本应用中，我们将研究树突状局部BDNF合成在控制能量平衡中的作用。目的1是确定瘦素是否调节树突状细胞中BDNF的局部合成。我们将使用绿色荧光蛋白报告结构和突触神经体准备来检测瘦素对树突状细胞转运和BDNF mRNA翻译的影响。目的2是确定VMH中树突合成的BDNF是否调节食物摄入量和体重。我们将尝试通过在VMH中病毒表达树突状局部BDNF mRNA或躯体定位BDNF mRNA来挽救缺乏树突状局部BDNF合成的BDNF突变体的肥胖表型。目的3是检测局部缺乏BDNF合成是否改变了表达TrkB的下丘脑神经元的树突棘的形态。在下丘脑弓状核(ARC)和下丘脑背内侧核(DMH)等对能量平衡的调控起重要作用的核团中有TrkB表达的神经元。我们将研究局部BDNF合成缺陷的小鼠突变体ARC和DMH中TrkB表达神经元的脊柱形态。公共卫生相关性识别和表征控制能量平衡的新分子和信号通路将为设计改进的肥胖治疗方法提供机会。如果成功，这个拟议项目的发现将表明，与树突状mRNA的运输和翻译有关的蛋白质突变将增加肥胖的易感性。因此，这些蛋白质可能成为治疗肥胖症的潜在药物靶点。

DESCRIPTION (provided by applicant): Brain-derived neurotrophic factor (BDNF) and its TrkB receptor have been implicated in the control of energy balance in both humans and mice. Previous studies suggest that BDNF expressed in the ventromedial hypothalamus (VMH) plays a critical role in regulating energy balance. BDNF protein is synthesized in both neuronal somas and dendrites. In this application, we will examine the role of dendritic local BDNF synthesis in the control of energy balance. Aim 1 is to determine if leptin regulates local synthesis of BDNF in dendrites. We will employ green fluorescence protein reporter constructs and synaptoneurosome preparations to examine the effect of leptin on dendritic transport and translation of BDNF mRNA. Aim 2 is to determine if dendritically synthesized BDNF in the VMH regulates food intake and body weight. We will attempt to rescue the obese phenotype in a Bdnf mouse mutant which lacks dendritic local BDNF synthesis through viral expression of dendritically localized BDNF mRNA or somatically localized BDNF mRNA in the VMH. Aim 3 is to examine if lack of local BDNF synthesis alters morphologies of dendritic spines of TrkB-expressing hypothalamic neurons. There are TrkB-expressing neurons in the hypothalamic nuclei important for the control of energy balance, such as the arcuate nucleus (ARC) and dorsomedial hypothalamus (DMH). We will examine spine morphologies of TrkB-expressing neurons in the ARC and DMH in the mouse mutant deficient in local BDNF synthesis. PUBLIC HEALTH RELEVANCE Identification and characterization of new molecules and signaling pathways that control energy balance will offer opportunities for designing improved obesity treatments. If successful, findings from this proposed project will suggest that mutations in proteins involved in transport and translation of dendritic mRNA will increase susceptibility to obesity. Therefore, these proteins could be potential drug targets for obesity treatment.