Leptin and Insulin Responses in Hypothalamic NPY Neurons

描述（由申请人提供）：肥胖从根本上说是一种能量平衡紊乱。成年人的体重通常通过神经和激素回路维持在一个狭窄的范围内，这些回路起着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的变化，如葡萄糖和游离脂肪酸，以及激素，如胰岛素和瘦素。在人类和其他哺乳动物中，这些外围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协调反应。一个这样的反馈回路，即下丘脑弓状核中的黑皮质素回路，由神经肽Y（NPY）表达神经元和阿黑皮素原（POMC）表达神经元组成，所述神经肽Y（NPY）表达神经元促进进食并减少能量消耗，所述阿黑皮素原（POMC）表达神经元抑制进食并增加能量消耗。然而，在神经肽Y神经元中激素感受的下游事件目前尚不清楚。本研究将探讨瘦素和胰岛素对神经肽Y神经元电活动的影响，以及可能介导这些影响的细胞内信号传导通路。确定这些途径可能会揭示对肥胖和2型糖尿病中这些信号的抵抗如何发生。 公共卫生相关性：肥胖成人和儿童的数量在全球范围内急剧增加，导致2型糖尿病、高血压、肝病和其他相关疾病的患病率平行增加。从根本上说，肥胖是一种神经和激素机制的紊乱，这些机制感知储存的能量的数量并适当地改变食物摄入和能量消耗;需要更好地了解这些机制，以开发安全降低体重和血糖的新疗法。该项目旨在揭示循环激素瘦素和胰岛素如何调节下丘脑黑皮质素系统的一个组成部分，这是一个控制体重和能量消耗的关键神经回路。

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. PUBLIC HEALTH RELEVANCE: The number of obese adults and children is increasing dramatically worldwide, driving parallel increases in the prevalence of type 2 diabetes mellitus, hypertension, liver disease, and other associated conditions. Fundamentally, obesity is a disorder of the neural and hormonal mechanisms that sense the quantity of stored energy and appropriately modify food intake and energy expenditure; a better understanding these mechanisms is required to develop new treatments that safely lower body weight and blood glucose. This project aims to reveal how the circulating hormones leptin and insulin regulate a component of the hypothalamic melanocortin system, a key neural circuit that controls body weight and energy expenditure.