Unraveling the role of PVH BDNF neurons in energy balance

摘要 这项研究项目的长期目标是了解调节能量平衡的机制。在……里面 2011-2012年，美国35%的成年人和17%的年轻人患有肥胖症。肥胖的青少年和成年人 患2型糖尿病的几率很高，并有严重威胁生命的心血管疾病的风险 疾病和癌症。阐明能量平衡的机制应该提供一个 有机会开发新的有效和非侵入性的治疗干预措施。脑源性 神经营养因子(BDNF)在调节能量平衡中起重要作用。脑源性神经营养因子基因的突变 它的受体TrkB会导致小鼠和人类的严重肥胖。此外，脑源性神经营养因子基因已经被 在全基因组关联研究中与人类肥胖有关。然而，我们目前知道的要少得多。 关于BDNF而不是瘦素和MC4R在这些分子的潜在作用机制方面 能量平衡的控制。为了帮助填补这一知识空白，这项研究项目测试了以下假设 脑源性神经营养因子在下丘脑室旁核表达的神经元整合与营养物质有关的信号， 能量储存和繁殖，并投射到下丘脑内和下丘脑外靶点以调节食欲 和能量消耗。这一假设是基于我们在前一次拨款期间所做的令人兴奋的发现。 时期：(1)PVH中BDNF基因的缺失导致棕色动物明显的吞噬功能亢进，产热功能受阻 脂肪组织(BAT)与重度肥胖；(2)PVHBDNF神经元通过多突触与BAT相连 脊髓交感节前神经元刺激适应性产热；(3)PVHBDNF 神经元也与白色脂肪组织(WAT)有多突触联系，这表明它们在诱导过程中起作用 (4)PVHBDNF神经元密集投射到下丘脑弓状核(ARH)， 下丘脑背内侧核(DMH)、臂旁外侧核腹侧区(LPBN)和丘脑背内侧核(LPBN) 除脊髓外，还有孤束核(NTS)；(5)PVHBDNF神经元接受ARH、DMH和 第三脑室吻侧脑室周围区(RP3V)。当PVHMC4R神经元从ARH和 密集投射至中央下丘脑束核、孤束核和迷走神经背侧运动核。 PVHBDNF神经元和PVHMC4R神经元有不同的投射靶点和输入来源，提示 这两组神经元在不同的环境中调节能量平衡。因此，迫切需要 描述脑源性神经营养因子抑制食欲和促进产热的神经回路，以便 充分认识能源平衡的集中调控。我们建议从三个具体的方面来检验我们的假设 目标。目标1是确定哪个PVHBDNF投影调节能量平衡；目标2是确定身份 和传入神经元对PVHBDNF神经元的作用；目的3研究PVHBDNF神经元在 在水中诱导米色脂肪细胞。拟议中的研究结果将揭示新的神经回路 调节食欲和适应性产热的物质。 好了！

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. !