Role of PTP1B in Body Mass Regulation

适当控制生物体的体重和成分对于生存至关重要。 这种调节障碍（例如肥胖）越来越常见，并且可能产生重要的医学后果，例如胰岛素抵抗/2型糖尿病和血脂异常/心血管疾病。直到最近，人们对体重调节知之甚少。 现在很清楚，脂肪细胞激素瘦素在调节体重/成分方面发挥着关键作用。瘦素通过瘦素受体 (LR) 发出信号，LR 是一种 I 型细胞因子受体，通过激活相关的 Janus 家族激酶、Jak2 和下游途径（包括 Stat3 和 Erk MAP 激酶）来传输信号。 LR 在关键的下丘脑核团上表达，这些核团通过神经肽的合成和分泌调节食物摄入和能量消耗，以及调节甲状腺激素、皮质类固醇和性类固醇产生的神经内分泌轴。 胰岛素受体（IR）也可能在体重调节中发挥重要作用。 IR 在下丘脑中表达，似乎具有促肛门/分解代谢作用。 蛋白酪氨酸磷酸酶 (PTP) 也是酪氨酰磷酸化的关键调节因子，但特定 PTP 在体重调节中的作用却完全不清楚。 最近，发现缺乏 PTP1B 的小鼠对胰岛素过敏，并且对饮食引起的肥胖具有抵抗力。 前者似乎是由于 PTP1B 对外周 IR 的调节，但 PTP1B-/- 小鼠为什么瘦仍然未知。我们的初步数据表明 PTP1B-/- 小鼠对瘦素过敏，并可能对胰岛素的中枢神经系统作用过敏。 生化研究表明PTP1B可以直接使Jak2去磷酸化。 我们假设 PTP1B 负向调节下丘脑 LR 和可能的 IR 信号传导，并且这种调节的丧失导致 PTP1B-/- 小鼠体重表型的改变。 为了检验这一假设，我们将采用生化、生理和遗传学相结合的方法来（1）进一步确定 PTP1B-/- 小鼠瘦素过敏的原因、机制和后果； (2) 确定 PTP1B 是否也调节下丘脑 IR 信号传导，如果是，则确定失去这种调节对 PTP1B-/- 小鼠体重表型的影响； (3) 创建 PTP1B 的诱导等位基因，并通过组织特异性敲除/重建策略，测试大脑和特定下丘脑区域中 PTP1B 丢失对 PTP1B-/- 体重表型的贡献。 拟议的研究是由 Barbara Kahn 博士发起的一项由研究者发起的互动研究项目资助的一部分，该项目的重点是 PTP1B 在调节外周胰岛素作用中的作用。 总之，我们的结果将对理解体重控制以及评估 PTP1B 作为肥胖和/或 2 型糖尿病治疗靶点的效用具有潜在的重要意义。

Proper control of an organism's body mass and composition is essential for survival. Disorders of this regulation (e.g., obesity) are increasingly common, and can have important medical consequences, such as insulin resistance/Type 2 diabetes mellitus, and dyslipidemias/cardiovascular disease. Until recently, relatively little was known about body mass regulation. It now is clear that the adipocyte hormone leptin plays a critical role in regulating body mass/composition. Leptin signals via the leptin receptor (LR), a type I cytokine receptor, which transmits signals by activating the associated Janus family kinase, Jak2 and downstream pathways, including Stat3 and the Erk MAP kinase. The LR is expressed on key hypothalamic nuclei that regulate food intake and energy expenditure via the synthesis and secretion of neuropeptides, as well as neuroendocrine axes that regulate production of thyroid hormone, corticosteroids and sex steroids. The insulin receptor (IR) may also have important roles in body mass regulation. The IR is expressed in the hypothalamus where it appears to have anorectogenic/catabolic effects. Protein tyrosine phosphatases (PTPs) also are key regulators of tyrosyl phosphorylation, yet the roles of specific PTPs in body mass regulation have been completely obscure. Recently, mice lacking PTP1B were found to be hypersensitive to insulin and resistant to diet-induced obesity. The former appears to be due to PTP1B regulation of IR in the periphery, but why PTP1B-/- mice are lean remains unknown. Our preliminary data indicate that PTP1B-/- mice are hypersensitive to leptin and possibly to the CNS actions of insulin. Biochemical studies show that PTP1B can directly dephosphorylate Jak2. We hypothesize that PTP1B negatively regulates hypothalamic LR and possibly, IR signaling and that loss of this regulation contributes to the altered body mass phenotype of PTP1B-/-mice. To test this hypothesis, we will use a combined biochemical, physiological, and genetic approach to (1) further define the causes, mechanism, and consequences of leptin hypersensitivity in PTP1B-/- mice; (2) determine whether PTP1B also regulates hypothalamic IR signaling and if so, the consequences of loss of this regulation on the body mass phenotype of PTP1B-/- mice; and (3) create an inducible allele of PTP1B and, by means of tissue-specific knockout/reconstitution strategies, test the contribution of loss of PTP1B in the brain and specific hypothalamic regions to the PTP1B-/- body mass phenotype. The proposed studies are part of an Investigator- Initiated Interactive Research Project Grant with Dr. Barbara Kahn, whose project focuses on the role of PTP1B in regulating insulin action in the periphery. Together, our results will have potentially important implications for understanding control of body mass, and for assessing the utility of PTP1B as a therapeutic target for obesity and/or Type 2 diabetes.