TrkB Neurons in the Control of Body Weight

TrkB 神经元控制体重

• 批准号: 9108676
• 负责人: BAOJI XU
• 金额: $ 60.91万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9108676
• 关键词: Acute; Adult; Body Weight; Brain region; Brain-Derived Neurotrophic Factor; CAV2 gene; Canine Adenoviruses; Cardiovascular Diseases; Cell Nucleus; Child; Clozapine; Consumption; Desire for food; Drug Targeting; Eating; Energy Intake; Energy Metabolism; Equilibrium; Food Energy; Food Intake Regulation; Gene Deletion; Gene Expression; Gene Expression Profiling; Genes; Genetic Recombination; Goals; Human; Hyperphagia; Hypothalamic structure; Infection; Injection of therapeutic agent; Intervention; Label; Lead; Leptin; Life; Ligands; Link; Location; LoxP-flanked allele; Malignant Neoplasms; Maps; Measures; Mediating; Melanocortin 4 Receptor; Molecular; Monitor; Morbid Obesity; Motor Activity; Mus; Neurons; Neurotransmitters; Neurotrophic Tyrosine Kinase Receptor Type 2; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxides; Pathway interactions; Physiological Processes; Play; Proteins; RNA; Rabies virus; Regulation; Research Project Grants; Risk; Role; Signal Pathway; Site; Synapses; System; Tamoxifen; Technology; Thermogenesis; Tracer; Transcript; United States; Viral; Viral Vector; Virus; adeno-associated viral vector; alpha-Melanocyte stimulating hormone; beta-Galactosidase; design; designer receptors exclusively activated by designer drugs; economic cost; energy balance; leptin receptor; neural circuit; neuromechanism; novel; novel therapeutic intervention; obesity in children; presynaptic; presynaptic neurons; public health relevance; receptor; research study

 DESCRIPTION (provided by applicant): The long-term goal of this research project is to understand the mechanism governing the central control of energy balance. Three ligand-receptor pairs have been shown to play a key role in the regulation of energy balance, as deficits in any of these three signaling pathways lead to severe obesity in humans and mice. They are leptin and leptin receptor, alpha-melanocyte-stimulating hormone and melanocortin-4 receptor (MC4R), and brain-derived neurotrophic factor (BDNF) and its receptor TrkB. Great progress has been made in understanding the neural mechanism by which the first two ligand-receptor pairs regulate energy balance. However, very little is known on how the BDNF-TrkB pathway regulates energy balance. Our preliminary studies found that deletion of the TrkB gene in the paraventricular hypothalamus (PVH) caused extreme hyperphagia and severe obesity and that TrkB deletion in the dorsomedial hypothalamus (DMH) led to modest hyperphagia, impaired thermogenesis, reduced locomotor activity, and obesity. These exciting observations lead us to posit that some neural circuits linked to PVHTrkB and DMHTrkB neurons play a key role in regulating appetite and energy expenditure. We propose to demonstrate an important role for PVHTrkB and DMHTrkB neurons in the control of energy balance by deleting the TrkB gene in the PVH and DMH and by activating TrkB neurons in these two nuclei with the DREADD technology, to identify the neural circuits that mediate the effect of TrkB expressed in the PVH and DMH on appetite and energy expenditure using viral tract tracing and projection-specific gene deletion, and to characterize PVHTrkB and DMHTrkB neurons through gene expression profiling.

 描述（申请人提供）：本研究项目的长期目标是了解能量平衡的中央控制机制。三种配体-受体对已被证明在能量平衡的调节中起关键作用，因为这三种信号通路中的任何一种的缺陷都会导致人类和小鼠的严重肥胖。它们是瘦素和瘦素受体、α-黑素细胞刺激激素和黑素皮质素-4受体（MC 4 R）以及脑源性神经营养因子（BDNF）及其受体TrkB。在理解前两对配体-受体调节能量平衡的神经机制方面已经取得了很大进展。然而，对BDNF-TrkB通路如何调节能量平衡知之甚少。我们的初步研究发现，室旁下丘脑（PVH）中TrkB基因的缺失导致极端的暴食症和严重的肥胖症，而背内侧下丘脑（DMH）中TrkB基因的缺失导致适度的暴食症，产热受损，运动活动减少和肥胖症。这些令人兴奋的观察使我们认识到，与PVHTrkB和DMHTrkB神经元相关的一些神经回路在调节食欲和能量消耗方面起着关键作用。我们建议通过删除PVH和DMH中的TrkB基因并通过DREADD技术激活这两个核团中的TrkB神经元来证明PVHTrkB和DMHTrkB神经元在控制能量平衡中的重要作用，使用病毒道追踪和投射特异性基因删除来鉴定介导PVH和DMH中表达的TrkB对食欲和能量消耗的影响的神经回路，并通过基因表达谱表征PVHTrkB和DMHTrkB神经元。