Unraveling the role of PVH BDNF neurons in energy balance

总结 该研究项目的长期目标是了解调节能量平衡的机制。在 2011 - 2012年，美国35%的成年人和17%的青年人肥胖。肥胖的青年和成年人 2型糖尿病的发病率很高， 疾病和癌症。阐明控制能量平衡的机制， 开发新的有效和非侵入性治疗干预的机会。脑源 神经营养因子（BDNF）在调节能量平衡中起关键作用。BDNF基因突变 及其受体TrkB导致小鼠和人类的严重肥胖。此外，BDNF基因已被 在全基因组关联研究中与人类肥胖相关。然而，我们目前知道的要少得多， 关于BDNF比瘦素和MC4R的机制，这些分子在 控制能量平衡。为了帮助填补这一知识空白，该研究项目测试了以下假设： 室旁下丘脑（PVHBDNF）中表达BDNF的神经元整合与营养相关的信号， 能量储存和繁殖，并投射到下丘脑内和外靶点以调节食欲 和能量消耗。这一假设是基于我们在先前的资助期间所做的令人兴奋的发现 （1）PVH中Bdnf基因的缺失导致了明显的摄食过度，棕色体产热能力减弱 （2）PVHBDNF神经元通过多突触连接到BAT， 脊髓交感节前神经元刺激适应性产热;（3）PVHBDNF 神经元也多突触连接到白色脂肪组织（WAT），表明它们在诱导中的作用 （4）PVHBDNF神经元密集投射至下丘脑弓状核（ARH）， 下丘脑背内侧核（DMH）、臂旁外侧核腹侧区（LPBN）和下丘脑核（DMH） 除脊髓外，还接受孤束（NTS）;（5）PVHBDNF神经元接受来自ARH、DMH和 第三脑室头侧脑室周区（RP3V）。当PVHMC4R神经元接收来自ARH的输入时， 投射到中央LPBN，NTS和迷走神经背核，我们的研究结果表明， PVHBDNF神经元和PVHMC4R神经元具有不同的投射靶点和输入源，表明 这两组神经元在不同的环境中调节能量平衡。因此，当务之急是 描述BDNF抑制食欲和促进产热的神经回路， 充分理解能量平衡的中央控制。我们建议在三个具体的测试我们的假设 目标。目的1是确定哪种PVHBDNF投射调节能量平衡;目的2是确定 目的3：探讨PVHBDNF神经元在大鼠海马神经元中的作用， 在WAT内诱导米色脂肪细胞。这项研究的结果将揭示新的神经回路 调节食欲和适应性产热。 !

Summary The long-term goal of this research project is to understand the mechanism that regulates energy balance. In the United States 35% of adults and 17% of youth are obese in 2011-2012. Obese youth and adults are developing type 2 diabetes at high rates and are at significant risk for life-threatening cardiovascular disease and cancer. Elucidation of the mechanism governing energy balance should provide an opportunity to develop novel effective and non-invasive therapeutic interventions. Brain-derived neurotrophic factor (BDNF) plays a critical role in regulating energy balance. Mutations in the genes for BDNF and its receptor TrkB lead to severe obesity in both mice and humans. Furthermore, the BDNF gene has been associated with human obesity in genome-wide association studies. However, we currently know much less about BDNF than leptin and MC4R with regard to the mechanisms underlying the role of these molecules in the control of energy balance. To help fill this knowledge gap, this research project tests the hypothesis that BDNF-expressing neurons in the paraventricular hypothalamus (PVHBDNF) integrate signals related to nutrients, energy store and reproduction, and project to both intra- and extra-hypothalamic targets to regulate appetite and energy expenditure. This hypothesis is based on the exciting findings we made during the prior grant period: (1) Deletion of the Bdnf gene in the PVH leads marked hyperphagia, impaired thermogenesis in brown adipose tissue (BAT) and severe obesity; (2) PVHBDNF neurons are polysynaptically connected to BAT through sympathetic preganglionic neurons in the spinal cord to stimulate adaptive thermogenesis; (3) PVHBDNF neurons are also polysynaptically connected to white adipose tissue (WAT), suggesting their role in induction of beige adipocytes; (4) PVHBDNF neurons project densely to the arcuate nucleus of the hypothalamus (ARH), dorsomedial hypothalamus (DMH), ventral region of the lateral parabrachial nucleus (LPBN) and nucleus of the solitary tract (NTS) in addition to the spinal cord; (5) PVHBDNF neurons receive inputs from the ARH, DMH and rostral periventricular region of the 3rd ventricle (RP3V). As PVHMC4R neurons receive input from the ARH and project densely to the central LPBN, NTS and dorsal motor nucleus of the vagus, our findings indicate that PVHBDNF neurons and PVHMC4R neurons have distinct projection targets and input sources, suggesting that these two groups of neurons regulate energy balance in different contexts. Therefore, it is imperative to delineate neural circuits through which BDNF suppresses appetite and promotes thermogenesis in order to fully understand the central control of energy balance. We propose to test our hypothesis in three specific aims. Aim 1 is to identify which PVHBDNF projection regulates energy balance; Aim 2 is to determine the identity and function of afferent neurons to PVHBDNF neurons; Aim 3 is to investigate the role of PVHBDNF neurons in induction of beige adipocytes within WAT. Findings from the proposed studies will uncover novel neural circuits that regulate appetite and adaptive thermogenesis. !