Unraveling the role of PVH BDNF neurons in energy balance

揭示 PVH BDNF 神经元在能量平衡中的作用

• 批准号: 9912758
• 负责人: BAOJI XU
• 金额: $ 59.31万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912758
• 关键词: Adipocytes; Adipose tissue; Adult; Affect; Afferent Neurons; BDNF gene; Blood Pressure; Body Weight; Brain region; Brain-Derived Neurotrophic Factor; Brown Fat; Cardiovascular Diseases; Cardiovascular system; Desire for food; Diabetes Mellitus; Energy Metabolism; Event; Expression Profiling; Gastrointestinal tract structure; Genes; Goals; Grant; Health; Heart Rate; Human; Hyperphagia; Hypothalamic structure; Impairment; In Situ Hybridization; Interneurons; Knowledge; Label; Lateral; Lead; Leptin; Life; Light; Malignant Neoplasms; Measures; Melanocortin 4 Receptor; Morbid Obesity; Morbidity - disease rate; Mus; Mutation; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Nutrient; Nutritional; Obesity; Pharmacology; Play; Pregnancy; Rabies virus; Regulation; Reproduction; Research; Research Project Grants; Risk; Role; Signal Pathway; Signal Transduction; Source; Spinal Cord; Structure of nucleus infundibularis hypothalami; Temperature; Testing; Therapeutic Intervention; Thermogenesis; United States; Virus; Youth; bariatric surgery; base; dorsal motor nucleus; effective therapy; energy balance; genome wide association study; neural circuit; novel; obesity treatment; parabrachial nucleus; receptor expression; side effect

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. !

概括 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，美国有35%的成年人和17%的青少年肥胖。肥胖的青少年和成人 2 型糖尿病发病率很高，并且存在危及生命的心血管疾病的重大风险 疾病和癌症。阐明能量平衡的机制应该提供一个 开发新型有效和非侵入性治疗干预措施的机会。脑源性 神经营养因子（BDNF）在调节能量平衡中起着至关重要的作用。 BDNF 基因突变 及其受体 TrkB 会导致小鼠和人类严重肥胖。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，我们目前所知甚少 与瘦素和 MC4R 相比，关于 BDNF 的作用机制 能量平衡的控制。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素相关的信号， 能量储存和再生，并投射到下丘脑内和下丘脑外目标以调节食欲 和能量消耗。这个假设是基于我们在之前的资助期间取得的令人兴奋的发现 时期：（1）PVH中Bdnf基因的缺失导致棕色动物显着的食欲过盛、生热作用受损 脂肪组织（BAT）和严重肥胖； (2) PVHBDNF神经元通过多突触与BAT连接 脊髓中的交感神经节前神经元刺激适应性产热； (3)PVHBDNF 神经元还与白色脂肪组织（WAT）多突触连接，表明它们在诱导中的作用 米色脂肪细胞； (4) PVHBDNF 神经元密集投射到下丘脑弓状核 (ARH)， 下丘脑背内侧 (DMH)、臂旁外侧核 (LPBN) 腹侧区和 除脊髓外还有孤束 (NTS)； (5) PVHBDNF 神经元接收来自 ARH、DMH 和 第三脑室的头侧脑室周围区域（RP3V）。当 PVHMC4R 神经元接收来自 ARH 的输入并 密集投射到中央 LPBN、NTS 和迷走神经的背运动核，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目标和输入源，这表明 这两组神经元在不同的情况下调节能量平衡。因此，当务之急是 描绘 BDNF 抑制食欲和促进产热的神经回路，以便 充分认识能量平衡的中央控制。我们建议在三个具体方面检验我们的假设 目标。目标 1 是确定哪个 PVHBDNF 预测调节能量平衡；目标2是确定身份 以及传入神经元对 PVHBDNF 神经元的功能；目标 3 是研究 PVHBDNF 神经元在 WAT 内米色脂肪细胞的诱导。拟议研究的结果将揭示新的神经回路 调节食欲和适应性产热。 ！