Regulation of energy homeostasis by BDNF

描述(由申请者提供)：本研究项目的长期目标是了解控制能量稳态的分子和神经机制。脑源性神经营养因子(BDNF)在能量平衡中起着至关重要的作用，因为BDNF及其受体TrkB的基因突变导致了小鼠和人类的肥胖；然而，BDNF在体重调节中的确切作用尚不清楚。下丘脑神经回路的组织和活动在能量平衡的控制中起着关键作用，而BDNF是神经元发育和突触可塑性的有力调节者。这项应用旨在验证BDNF通过调节下丘脑内侧基底神经回路的形成来控制体重的假设，这些神经回路已知的控制能量平衡。轴突生长、突触发生和脊柱发育的缺陷将改变下丘脑回路的发育，这反过来将损害下丘脑对反映营养和脂肪储存状态的信号的整合。目的1确定弓状核(ARC)中TrkB表达的神经元是否对摄食状态的变化做出反应，并采用体内和体外方法研究BDNF是否调节这些神经元的轴突生长。目的2利用突触前标志物的免疫组织化学和全细胞膜片钳记录，研究BDNF是否对表达神经肽Y或前阿片黑素皮质素的ARC神经元的兴奋性和抑制性突触的形成有不同的调节作用。目的3将确定是否需要下丘脑背内侧(DMH)中的TrkB来控制能量平衡，以及在缺乏局部BDNF合成并发展为严重肥胖的突变小鼠中，表达TrkB的DMH神经元上树突棘的数量和形状是否发生改变。这项拟议项目的发现将为BDNF调节能量平衡的机制以及下丘脑神经回路结构变化在肥胖发展中的作用提供洞察力。 公共卫生相关性：由于肥胖症的高流行率和相关疾病，肥胖已成为该国的主要健康问题。尽管肥胖带来了巨大的经济成本，但目前还没有有效的肥胖治疗方法。为了开发有效和安全的抗肥胖疗法，需要继续进行研究，以了解调节能量稳态的分子、细胞和生理过程。

DESCRIPTION (provided by applicant): The long-term goal of this research project is to understand the molecular and neural mechanisms governing energy homeostasis. Brain-derived neurotrophic factor (BDNF) plays crucial roles in energy balance, as mutations in the genes for BDNF and its receptor TrkB lead to obesity in both mice and humans; however, the precise role of BDNF in the regulation of body weight remains unknown. The organization and activity of hypothalamic neural circuits plays a critical role in the control of energy balance and BDNF is a potent regulator of neuronal development and synaptic plasticity. This application proposes to test the hypothesis that BDNF controls body weight by regulating the formation of neural circuits in the mediobasal hypothalamus that are known to control energy balance. Defects in axonal growth, synaptogenesis, and spine development will alter the development of hypothalamic circuits, which will in turn impair hypothalamic integration of signals reflecting states of nutrition and fat stores. Aim 1 will determine if TrkB-expressing neurons in the arcuate nucleus (ARC) respond to changes in feeding status and investigate if BDNF regulates axonal growth of these neurons using both in vivo and in vitro approaches. Aim 2 will investigate if BDNF differentially regulates the formation of excitatory and inhibitory synapses in ARC neurons expresing either neuropeptide Y or proopiomelanocortin using both immunohistochemistry against presynaptic markers and whole-cell patch-clamp recordings. Aim 3 will determine if TrkB in the dorsomedial hypothalamus (DMH) is required for the control of energy balance and if the number and shape of dendritic spines on TrkB-expressing DMH neurons are altered in mutant mice that lack local BDNF synthesis and develop severe obesity. Findings from this proposed project would provide insights into the mechanism by which BDNF regulates energy balance as well as the role of structural changes in hypothalamic neural circuits in the development of obesity. PUBLIC HEALTH RELEVANCE: Obesity has become a leading health issue in this country due to its high prevalence and associated disorders. Despite the enormous economic cost of obesity, no effective treatments for obesity are currently available. Continuing research efforts to understand the molecular, cellular, and physiological processes regulating energy homeostasis are needed in order to develop effective and safe anti-obesity therapies.