Regulation of Insulin and Leptin Action by Neuronal SOCS3

肥胖是一种日益普遍的调节能量平衡的系统紊乱，具有严重的病态后果。能量平衡和体重的生理调节涉及下丘脑神经回路，其响应于外周激素，包括脂肪细胞激素瘦素和β细胞激素胰岛素。几乎所有的啮齿动物和人类肥胖的特点是抵抗瘦素和胰岛素的作用。虽然引起抵抗的机制还没有很好地理解，但这些途径可能在很大程度上负责肥胖和糖尿病的易感性，并且拮抗引起瘦素和胰岛素抵抗的途径可能会产生实质性的治疗益处。细胞因子信号转导抑制 信号传导3（SOCS3）是一种在细胞和组织中由瘦素和胰岛素诱导的分子，在肥胖动物的组织中表达增加，并且能够拮抗瘦素和胰岛素的信号传导。因此，它是肥胖和糖尿病的潜在分子介质。该提案的目标是确定SOCS3作为正常和肥胖小鼠脑中胰岛素和瘦素信号传导和作用的负调节剂的生物学功能。在具体的目标1中，我们将尝试理解SOCS3在瘦素信号传导中的作用以及在CMS中的作用，使用神经元中具有SocsS条件性缺失的小鼠。我们将确定神经元缺失SOCSS对下丘脑瘦素信号传导的影响，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外周组织AMPK活性的作用。在目标2中，我们将尝试类似的实验来阐明SOCSS在CMS中调节胰岛素作用的作用。在目标3中，我们将创建模型，其中SOCSS从POMC和AgRP神经元中过表达或缺失，以确定SOCSS在这些神经元能量平衡功能中的特定作用。

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.