Regulation of Insulin and Leptin Action by Neuronal SOCS3

肥胖是一种越来越普遍的能量平衡调节系统紊乱，具有严重的病态后果。能量平衡和体重的生理调节涉及对外周激素做出反应的下丘脑神经回路，包括脂肪细胞激素瘦素和β细胞激素胰岛素。几乎所有啮齿动物和人类肥胖的特征都是对瘦素和胰岛素的作用产生抵抗。尽管引起抵抗的机制还不清楚，但这些途径很可能在很大程度上导致肥胖和糖尿病的易感性，而拮抗导致瘦素和胰岛素抵抗的途径可能会产生实质性的治疗益处。细胞因子抑制因子 信号转导3(SOCS3)是一种在细胞和组织中由瘦素和胰岛素诱导的分子，在肥胖动物组织中表达增加，并能够拮抗瘦素和胰岛素的信号转导。因此，它是肥胖和糖尿病的潜在分子介体。这项建议的目的是确定SOCS3作为胰岛素和瘦素信号的负调节因子的生物学功能以及在正常和肥胖小鼠大脑中的作用。在特定的目标1，我们将试图了解SOCS3在瘦素信号中的作用以及在CMS中的作用，使用在神经元中有条件地缺失SOCS3的小鼠。我们将确定SOCS神经元缺失对下丘脑瘦素信号转导的影响，瘦素对食物摄入、能量消耗和葡萄糖稳态的作用，以及瘦素对下丘脑和周围组织AMPK活性的影响。在目标2中，我们将尝试类似的实验，以阐明SOCS在调节CMS中的胰岛素作用方面的作用。在目标3中，我们将建立SOCS在POMC和AgRP神经元中过度表达或缺失的模型，以确定SOCS在这些神经元的能量平衡功能中的具体作用。

Obesity is an increasingly prevalent disorder of the system for regulating energy balance that has major morbid consequences. The physiologic regulation of energy balance and body weight involves hypothalamic neural circuits that respond to peripheral hormones, including the adipocyte hormone leptin and the beta cell hormone insulin. Nearly all rodent and human obesity is characterized by resistance to the actions of leptin and insulin. Although the mechanisms causing resistance are not well understood, these pathways are likely responsible in significant measure for susceptibility to obesity and diabetes, and antagonizing the pathways causing leptin and insulin resistance would likely yield substantial therapeutic benefit. Suppressor of cytokine signaling 3 (SOCS3) is a molecule that is induced by leptin and insulin in cells and tissues, is increased in expression in tissues of obese animals, and is capable of antagonising signaling by both leptin and insulin. It is therefore a potential molecular mediator of both obesity and diabetes. The goal of this proposal is to determine the biological function of SOCS3 as a negative regulator of insulin and leptin signaling and action in the brain of normal and obese mice. In specific aim 1, we will attempt to understand the role of SOCS3 in leptin signaling and action in the CMS, using mice with conditional deletion of SocsS in neurons. We will determine the consequences of neuronal deletion of SOCSS for leptin signaling in hypothalamus, leptin actions on food intake, energy expenditure and glucose homeostasis, and leptin action on AMPK activity in hypothalamus and peripheral tissues. In aim 2, we will attempt similar experiments to clarify the role of SOCSS in regulating insulin action in the CMS. In aim 3, we will create models in which SOCSS is either overexpressed, or deleted, from POMC and AgRP neurons, to determine the specific role of SOCSS in the function of these neurons in energy balance.