Neuronal Protein Tyrosine Phosphatases in Metabolism

描述（由申请人提供）：肥胖和合并症（如II型糖尿病）的患病率不断增加，在全球范围内构成了严重的健康问题。了解这些病理状态下的细胞信号通路对于帮助开发这些病症的潜在治疗方法至关重要。瘦素是一种由脂肪分泌的激素，作用于中枢神经系统（CNS）的神经元，调节食物摄入和能量消耗。瘦素启动细胞内信号级联反应，进而导致离子通道活性和基因表达的变化，最终保持能量平衡。瘦素信号通路受酪氨酸磷酸化的严格控制，最近发现两种蛋白酪氨酸磷酸酶（PTPs）参与了脑中瘦素信号通路的调节：PTP 1B和SHP 2。这些PTP在调节能量平衡方面显然具有重要的体内作用，但在细胞水平上精确的神经元作用位点和PTP 1B/SHP 2作用机制尚不清楚。下丘脑的POMC和AgRP神经元是能量平衡和葡萄糖稳态调节的重要部位。我们推测，PTP 1B和SHP 2具有重要的代谢作用，特别是在这些神经元通过瘦素依赖或独立的影响。我们的具体目标是解决PTP 1B或SHP 2缺失的影响，特别是在POMC或AgRP表达的神经元的小鼠体重，肥胖，瘦素敏感性，和葡萄糖耐量。此外，这些研究将解决PTP 1B或SHP 2缺失下丘脑神经元如何影响这些神经元的电生理特性。遗传学、生物化学和电生理学技术的这种结合将提供关于下丘脑神经元中PTP作用的细胞机制的基本信息，其与能量平衡有关。公共卫生相关性：肥胖和相关疾病，如II型糖尿病，正在以惊人的速度在世界各地增加。这些拟议的实验将研究有助于瘦素抵抗发展的细胞机制，瘦素抵抗是一种可导致肥胖和II型糖尿病的病理状态。我们推测，下丘脑中蛋白酪氨酸磷酸酶的信号调节是调节神经元能量平衡控制的细胞信号通路的重要组成部分。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Obesity and associated diseases such as type II diabetes are increasing at an alarming rate throughout the world. These proposed experiments will investigate the cellular mechanisms contributing to the development of leptin resistance, a pathological state which can lead to obesity and type II diabetes. We hypothesize that regulation of signaling by protein tyrosine phosphatases in the hypothalamus is an important component of the cellular signaling pathways regulating neuronal control of energy balance.