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介质，神经回路功能障碍被认为是肥胖的基础 发病机制在大脑中，下丘脑外侧区（LHA）控制进食行为， 体重由于其相当大的分子和功能的复杂性，LHA神经元的作用， 饮食诱导的肥胖症（DIO）的发展仍然知之甚少。解决LHA管理机制 进食行为以及它们在DIO期间如何重塑将有助于开发更有针对性的治疗方法， 干预肥胖症。我们的首要目标是获得LHA神经元的机制理解 DIO中的功能障碍。我们以前的工作已经证明，两个最丰富的细胞类型在LHA- 多巴胺能（LHAGlut）和GABA能（LHAGABA）神经元通过DIO转录重构。LHAGlut和 LHAGABA神经元在功能上相互对立：LHAGlut神经元抑制进食并减轻体重， 而LHAGABA神经元促进进食并增加体重。我们的初步数据证实LHAGlut 和LHAGABA神经元在能量状态的急性操纵过程中表现出相反的活动变化，并表现出 在DIO过程中的相反转录变化。这些结果突出了LHA神经元功能障碍的潜在作用 导致暴饮暴食和DIO然而，LHAGlut和LHAGABA神经元的潜在机制 DIO功能障碍是未知的。影响能量稳态、摄食行为和LHA的一个因素 活性是葡萄糖。因此，我们假设对葡萄糖的反应性的改变有助于LHAGlut和 急性和慢性营养过剩中LHAGABA神经元功能障碍以及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。为了验证这一点，我们将确定 使用纵向多光子体内成像的DIO中LHAGlut和LHAGABA神经元重塑的动力学， 电生理学然后我们将检验葡萄糖改变LHAGlut和LHAGABA活性的假设 神经元在体内急性和慢性过度喂养后。最后，我们将测试LHAGlut恢复的假设， 而LHAGABA神经元的活动可以逆转慢性营养过剩的不良后果。的结果 该项目将推进我们对大脑参与DIO的概念性理解，并确定新的 用于治疗进食障碍和肥胖症的治疗靶点。

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.