Neuronal Protein Tyrosine Phosphatases in Metabolism

肥胖症和II型糖尿病等并存疾病的日益流行构成了 世界范围内的重大健康问题。了解潜在的细胞信号通路 这些病理状态对于开发潜在的治疗方法是至关重要的。 这些条件。瘦素是一种由脂肪分泌的激素，作用于中枢神经系统的神经元。 神经系统(CNS)调节食物摄入量和能量消耗。瘦素启动一种 细胞内信号级联，进而导致离子通道活性和基因的变化 最终保持能量平衡的表情。瘦素信号通路密切相关 由酪氨酸磷酸化控制，有两个蛋白酪氨酸磷酸酶(PTPs) 最近被发现与大脑中瘦素信号通路的调节有关：PTP1B和 Shp2.这些PTP显然在体内调节能量平衡方面具有重要作用，但 神经元的精确作用部位(S)及PTP1B/SHP2在细胞水平的作用机制 都是未知的。下丘脑的POMC和AgRP神经元是两者的重要部位 能量平衡和葡萄糖动态平衡调节。我们假设PTP1B和SHP2 有重要的代谢作用，特别是通过瘦素依赖或- 独立效果。我们的具体目标将解决PTP1B或SHP2缺失的影响 体重、肥胖、瘦素对小鼠POMC或AgRP表达神经元的特异性影响 敏感度和葡萄糖耐量。此外，这些研究将讨论PTP1B或 下丘脑神经元Shp2缺失影响这些神经元的电生理特性 神经元。这种遗传、生化和电生理技术的结合将 提供有关下丘脑PTP作用的细胞机制的基本信息 神经元与能量平衡有关。

The increasing prevalence of obesity and co-morbidities such as type II diabetes poses a significant health problem worldwide. Understanding the cellular signaling pathways underlying these pathological states is critical to assist in developing potential therapeutic treatment of these conditions. Leptin is a hormone secreted by fat, which acts on neurons in the central nervous system (CNS) to regulate food intake and energy expenditure. Leptin initiates an intracellular signaling cascade which in turn leads to changes in ion channel activity and gene expression that ultimately keep energy balance in check. The leptin signaling pathway is tightly controlled by tyrosine phosphorylation, and two protein tyrosine phosphatases (PTPs) have recently been implicated in regulation of the leptin signaling pathway in the brain: PTP1B and SHP2. These PTPs clearly have important in vivo roles in regulating energy balance, but the precise neuronal site(s) of action and the mechanism of PTP1B/SHP2 action at a cellular level are unknown. POMC and AgRP neurons in the hypothalamus are an important site of both energy balance and glucose homeostasis regulation. We hypothesize that PTP1B and SHP2 have important metabolic roles specifically in these neurons via either leptin-dependent or - independent effects. Our specific aims will address the effects of PTP1B or SHP2 deletion specifically in POMC- or AgRP-expressing neurons of mice on body weight, adiposity, leptin sensitivity, and glucose tolerance. Furthermore, these studies will address how PTP1B or SHP2 deletion in hypothalamic neurons affects the electrophysiological properties of these neurons. This combination of genetic, biochemical, and electrophysiological techniques will provide essential information about the cellular mechanism of PTP action in hypothalamic neurons as relates to energy balance.