Neuronal Protein Tyrosine Phosphatases in Metabolism

描述（由申请人提供）：肥胖和II型糖尿病的发病率在全球范围内以惊人的速度上升，突出了了解这些病理条件下的分子事件的迫切需要。中枢神经系统的关键区域内的细胞信号传导途径已被鉴定为介导多种代谢过程，包括瘦素、胰岛素和脑源性神经营养因子（BDNF）信号传导途径。对这些CNS信号通路的调节至关重要的快速可逆磷酸化事件的破坏改变了它们对能量平衡和葡萄糖稳态的影响，从而促成肥胖和糖尿病的发病机制。一些蛋白酪氨酸磷酸酶（PTPs）已被确定为中枢瘦素信号传导的重要调节因子，然而这些PTPs如何动态地合作来调节瘦素信号传导或调节能量平衡的替代信号传导途径仍不清楚。蛋白酪氨酸磷酸酶1B（PTP 1B）是瘦素信号传导和CNS代谢控制的重要调节剂;具有全脑或神经元特异性PTP 1B缺陷的小鼠是瘦的和瘦素超敏的，并且显示增加的能量消耗和改善的葡萄糖稳态。最近，酪氨酸磷酸酶β 1（RPTPe）也被证明是瘦素信号传导的负调节因子，这增加了一种有趣的可能性，即PTP 1B和RPTPe缺乏可能具有协同的有益代谢效应。在该提议中，将评估化合物PTP 1B-和RPTPe-缺乏对瘦素信号传导、能量平衡和葡萄糖稳态的影响。值得注意的是，在初步研究中，我们确定了TrkB受体作为PTP 1B的一种新底物，并表明PTP 1B-/-小鼠对中枢BDNF递送表现出增强的代谢反应。因此，我们将测试新的假设，即PTP 1B是一个生理相关的调节BDNF信号通路在特定的中枢神经系统网站在体内和PTP 1B缺陷将增强BDNF/TrkB信号，并导致改善能量平衡。最后，PTP 1B表达在肥胖啮齿动物的大脑中升高;然而，尚不清楚增加的中央PTP 1B本身是否促进肥胖和葡萄糖耐受不良，或者涉及哪些关键的大脑区域和信号通路。一种新的小鼠模型的诱导型PTP 1B表达将被用来测试的假设，有针对性的神经元诱导的PTP 1B表达的关键中枢神经系统网站将促进肥胖和葡萄糖耐量受损。总的来说，拟议的研究将提供大量的新的见解蛋白酪氨酸磷酸酶在关键的中枢神经系统代谢信号通路的代谢功能，是高度相关的治疗人类肥胖症和II型糖尿病。

DESCRIPTION (provided by applicant): The rates of obesity and type II diabetes are rising at an alarming rate worldwide, highlighting the pressing need to understand the molecular events underlying these pathological conditions. Cellular signaling pathways within key areas of the central nervous system have been identified that mediate a multitude of metabolic processes, including the leptin, insulin and brain-derived neurotrophic factor (BDNF) signaling pathways. Disruption of the rapid reversible phosphorylation events critical for regulation of these CNS signaling pathways alter their influence on energy balance and glucose homeostasis, thereby contributing to the pathogenesis of obesity and diabetes. Several protein tyrosine phosphatases (PTPs) have been identified as important regulators of central leptin signaling, yet how these PTPs cooperate dynamically to regulate leptin signaling or alternative signaling pathways that regulate energy balance remains unclear. The protein tyrosine phosphatase 1B (PTP1B) is an important regulator of leptin signaling and CNS control of metabolism; mice with whole brain or neuron-specific deficiency of PTP1B are lean and leptin hypersensitive, and display increased energy expenditure and improved glucose homeostasis. Recently, the tyrosine phosphatase epsilon (RPTPe) was also shown to be negative regulator of leptin signaling, raising the interesting possibility that PTP1B and RPTPe-deficiency may have synergistic beneficial metabolic effects. In this proposal the effects of compound PTP1B- and RPTPe-deficiency on leptin signaling, energy balance and glucose homeostasis will be assessed. Notably, in preliminary studies we identify the TrkB receptor as a novel substrate of PTP1B and show that PTP1B-/- mice display enhanced metabolic responses to central BDNF delivery. Thus, we will test the novel hypothesis that PTP1B is a physiologically relevant regulator of the BDNF signaling pathway at specific CNS sites in vivo and that PTP1B-deficiency will enhance BDNF/TrkB signaling and lead to improved energy balance. Finally, PTP1B expression is elevated in the brain of obese rodents; however, it is not clear whether increased central PTP1B per se promotes obesity and glucose intolerance, or which key brain regions and signaling pathways are involved. A novel mouse model of inducible PTP1B expression will be utilized to test the hypothesis that targeted neuronal induction of PTP1B expression within key CNS sites will promote obesity and impair glucose tolerance. Overall the proposed research will provide substantial new insight into the metabolic functions of protein tyrosine phosphatases in key CNS metabolic signaling pathways, and is highly relevant to the treatment of human obesity and type II diabetes.