Lateral Hypothalamic circuit dysfunction underlying the development of diet-induced obesity

项目摘要 大脑是能量平衡的关键媒介，神经回路功能障碍被认为是肥胖的原因 发病机制。在大脑内，下丘脑外侧区(LHA)控制摄食行为和 体重。由于其相当大的分子和功能复杂性，LHA神经元在 饮食诱导肥胖(DIO)的发展仍然知之甚少。解决LHA机制治理 进食行为及其在DIO期间如何改变将有助于开发更有针对性的治疗方法 对肥胖的干预。我们的首要目标是从机制上理解LHA神经元 DIO的功能障碍。我们之前的工作已经证明，LHA中最丰富的两种细胞类型-- 谷氨酸能(LHAGlut)和GABA能(LHAGABA)神经元-由DIO转录重塑。LHAGlut和 LHAGABA神经元在功能上相互对立：LHAGlut神经元抑制摄食和减轻体重， 而LHAGABA神经元促进摄食和增加体重。我们的初步数据证实LHAGlut 而LHAGABA神经元在能量状态的急性操作中表现出相反的活动变化，并表现出 在DIO过程中对手转录的变化。这些结果突出了LHA神经元功能障碍的潜在作用 作为暴饮暴食和酒后驾车的原因。然而，LHAGlut和LHAGABA神经元的机制 DIO的功能障碍尚不清楚。影响能量平衡、摄食行为和LHA的一个因素 活动是葡萄糖。因此，我们假设对葡萄糖的反应性改变有助于LHAGlut和 急性和慢性营养过剩时LHAGABA神经元功能障碍和LHA神经元活性的恢复可以 逆转DIO中观察到的代谢和行为障碍。为了测试这一点，我们将确定时间 应用体内纵向多光子成像技术研究DIO中LHAGlut和LHAGABA神经元重构的动态变化 电生理学。然后我们将检验葡萄糖改变LHAGlut和LHAGABA活性的假设 急性和慢性过量喂养后体内的神经元。最后，我们将检验LHAGlut恢复的假设 LHAGABA神经元活性可以逆转慢性营养过剩的不良后果。这样做的结果 该项目将促进我们对大脑参与DIO的概念性理解，并确定 饮食失调和肥胖症的治疗目标。

Project Summary The brain is a critical mediator of energy homeostasis, and neurocircuit dysfunction is thought to underlie obesity pathogenesis. Within the brain, the lateral hypothalamic area (LHA) exerts control over feeding behavior and body weight. Because of its considerable molecular and functional complexity, the role of LHA neurons in the development of diet-induced obesity (DIO) is still poorly understood. Addressing the LHA mechanisms governing feeding behavior and how they are remodeled during DIO will help to develop more targeted therapeutic interventions for obesity. Our overarching goal is to gain a mechanistic understanding of LHA neuronal dysfunction in DIO. Our previous work has demonstrated that the two most abundant cell types in the LHA— glutamatergic (LHAGlut) and GABAergic (LHAGABA) neurons—are transcriptionally remodeled by DIO. LHAGlut and LHAGABA neurons functionally oppose one another: LHAGlut neurons suppress feeding and reduce body weight, whereas LHAGABA neurons promote feeding and increase body weight. Our preliminary data confirm that LHAGlut and LHAGABA neurons show opposing changes in activity during acute manipulations of energy state and exhibit opponent transcriptional changes during DIO. These results highlight a potential role for LHA neuron dysfunction as a cause for overeating and DIO. However, the mechanisms underlying LHAGlut and LHAGABA neuron dysfunction in DIO are unknown. One factor that influences energy homeostasis, feeding behavior, and LHA activity is glucose. We therefore hypothesize that alterations in responsivity to glucose contribute to LHAGlut and LHAGABA neuron dysfunction in acute and chronic overnutrition and that restoration of LHA neuron activity can reverse the metabolic and behavioral impairments observed in DIO. To test this, we will determine the temporal dynamics of LHAGlut and LHAGABA neuron remodeling in DIO using longitudinal multiphoton in vivo imaging and electrophysiology. We will then test the hypothesis that glucose changes the activity of LHAGlut and LHAGABA neurons in vivo after acute and chronic overfeeding. Finally, we will test the hypothesis that restoration of LHAGlut and LHAGABA neuron activity can reverse the adverse consequences of chronic overnutrition. The results of this project will advance our conceptual understanding of the brain's involvement in DIO and identify novel therapeutic targets for the treatment of eating disorders and obesity.