Leptin and Insulin Responses in Hypothalamic NPY Neurons

描述（申请人提供）：肥胖本质上是一种能量平衡紊乱。成年人的体重通常由神经和激素回路维持在一个狭窄的范围内，这些回路起到平衡能量摄入和消耗的作用。为了实现这种平衡，中枢神经系统感知并响应循环代谢物（如葡萄糖和游离脂肪酸）和激素（如胰岛素和瘦素）的变化。在人类和其他哺乳动物中，这些外周信号由下丘脑的神经回路整合，然后通过投射到其他大脑区域来协调反应。其中一个反馈回路是下丘脑弓状核中的黑素皮质素回路，由表达神经肽Y （NPY）的神经元和表达促阿片黑色素皮质素（POMC）的神经元组成，前者促进摄食并减少能量消耗，后者抑制摄食并增加能量消耗。然而，NPY神经元中激素感知的下游事件目前尚不清楚。本项目将研究NPY神经元对瘦素和胰岛素的急性电活动变化，以及可能介导这些影响的细胞内信号素途径。确定这些途径可能会揭示肥胖症和2型糖尿病患者对这些信号的抵抗是如何发生的。

DESCRIPTION (provided by applicant): Obesity is fundamentally a disorder of energy balance. Adult body weight is normally maintained within a narrow range by neural and hormonal circuits which act to balance energy intake and expenditure. To accomplish this balancing act, the central nervous system senses and responds to changes in circulating metabolites, such as glucose and free fatty acids, and hormones, such as insulin and leptin. In humans and other mammals, these peripheral signals are integrated by neural circuits in the hypothalamus, which then coordinate responses via projections to other brain regions. One such feedback circuit, the melanocortin circuit in the arcuate nucleus of the hypothalamus, consists of neuropeptide Y (NPY)-expressing neurons, which promote feeding and decrease energy expenditure, and pro-opiomelanocortin (POMC)-expressing neurons, which inhibit feeding and increase energy expenditure. However, the downstream events of hormone sensing in NPY neurons are presently unclear. This project will investigate the acute changes in electrical activity of NPY neurons in response to leptin and insulin and the intracellular signalin pathway that may mediate these effects. Determining these pathways may reveal insights into how resistance to these signals occurs in obesity and type 2 diabetes.