Regulation of food intake and body weight by dendritically synthesized BDNF

描述（由申请人提供）：脑源性神经营养因子（BDNF）及其TrkB受体与人类和小鼠的能量平衡控制有关。先前的研究表明，BDNF在下丘脑腹内侧（VMH）表达，在调节能量平衡中起关键作用。BDNF蛋白在神经元体和树突中合成。在这个应用中，我们将研究树突局部BDNF合成在能量平衡控制中的作用。目的1是确定瘦素是否调节树突中BDNF的局部合成。我们将采用绿色荧光蛋白报告蛋白构建和突触eurosome制备来检测瘦素对BDNF mRNA树突转运和翻译的影响。目的2是确定VMH中树突合成的BDNF是否调节食物摄入和体重。我们将尝试通过病毒在VMH中表达树突定位的Bdnf mRNA或体定位的Bdnf mRNA来挽救缺乏树突局部Bdnf合成的Bdnf小鼠突变体的肥胖表型。目的3是研究缺乏局部BDNF合成是否会改变表达trkb的下丘脑神经元树突棘的形态。下丘脑核中有表达trkb的神经元，如弓状核（ARC）和下丘脑背内侧核（DMH），对能量平衡的控制起重要作用。我们将在缺乏局部BDNF合成的小鼠突变体中检查ARC和DMH中表达trkb的神经元的脊柱形态学。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提供机会。如果成功，这个项目的研究结果将表明，参与树突mRNA转运和翻译的蛋白质突变将增加对肥胖的易感性。因此，这些蛋白质可能是肥胖治疗的潜在药物靶点。

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.