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 美国有35％的成年人和17％的年轻人在2011 - 2012年肥胖。肥胖的青年和成人是 以高率开发2型糖尿病，并且有危及生命的心血管的危险 疾病和癌症。阐明控制能量平衡机制应提供 开发新颖有效和非侵入性治疗干预措施的机会。大脑衍生 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基因的突变 它的受体TRKB导致小鼠和人类的严重肥胖。此外，BDNF基因已经 与人类肥胖有关，在全基因组关联研究中。但是，我们目前对 关于这些分子在这些分子中的作用的机制，大约比瘦素和MC4R。 能量平衡的控制。为了填补这一知识差距，该研究项目检验了以下假设 旁丘脑下丘脑（PVHBDNF）中表达BDNF的神经元，使与营养相关的信号整合 能源商店和繁殖，并投影到诸念和超丘脑的靶标，以调节食欲 和能量支出。该假设是基于我们在上一笔赠款期间提出的激动人心的发现 周期：（1）在PVH导线中删除BDNF基因标记为倍率，棕色的热发生受损 脂肪组织（蝙蝠）和严重的肥胖症； （2）PVHBDNF神经元通过多突触连接到蝙蝠通过 脊髓中的交感神经前神经元，以刺激适应性生热； （3）PVHBDNF 神经元还与白色脂肪组织（WAT）相连，表明它们在诱导中的作用 米色脂肪细胞； （4）PVHBDNF神经元密集地向下丘脑（ARH）的弓形核突出。 背侧下丘脑（DMH），外侧甲核的腹侧区域（LPBN）和核的核 除脊髓外，孤立道（NTS）； （5）PVHBDNF神经元从ARH，DMH和 三个心室（RP3V）的脑室环区域。由于PVHMC4R神经元从ARH接收输入， 密集地向中央LPBN，NTS和迷走神经的背运动核项目，我们的发现表明 PVHBDNF神经元和PVHMC4R神经元具有独特的投影靶标和输入来源，这表明 这两组神经元在不同情况下调节能量平衡。因此，必须 描绘神经回路通过，BDNF抑制食欲并促进热生成，以便 充分了解能量平衡的中心控制。我们建议在三个特定的特定中检验我们的假设 目标。目的1是确定哪种PVHBDNF投影调节能量平衡；目标2是确定身份 传入神经元对PVHBDNF神经元的功能； AIM 3是研究PVHBDNF神经元在 WAT内诱导米色脂肪细胞。拟议的研究的发现将发现新的神经回路 调节食欲和自适应生热。 呢