Role of PTP1B in Body Mass Regulation

适当控制生物体的质量和组成对生存是至关重要的。这一调节的紊乱(如肥胖)越来越常见，并可能产生重要的医学后果，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，人们对体重调节的了解还相对较少。现在很清楚，脂肪细胞荷尔蒙瘦素在调节身体质量/成分方面起着关键作用。瘦素通过瘦素受体(LR)传递信号，瘦素受体是一种I型细胞因子受体，通过激活相关的Janus家族激酶、JAK2和下游通路，包括STAT3和Erk MAP激酶来传递信号。LR表达在下丘脑的关键核团上，这些核团通过神经肽的合成和分泌来调节食物的摄取和能量消耗，以及调节甲状腺激素、皮质类固醇和性类固醇的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在下丘脑表达，在那里它似乎有肛门直肠/分解代谢的作用。蛋白酪氨酸磷酸酶(PTPs)也是酪氨酸磷酸化的关键调节因子，但其在体重调节中的作用尚不清楚。最近，缺乏PTP1B的小鼠被发现对胰岛素高度敏感，对饮食诱导的肥胖具有抵抗力。前者似乎是由于PTP1B对外周IR的调节，但为什么PTP1B-/-小鼠很瘦仍不清楚。我们的初步数据表明，PTP1B-/-小鼠对瘦素和可能对胰岛素的中枢神经系统的作用都很敏感。生化研究表明，PTP1B可以直接去磷酸化JAK2。我们假设PTP1B负性调节下丘脑LR和可能的IR信号，并且这一调节的缺失有助于PTP1B-/-小鼠体质量表型的改变。为了验证这一假说，我们将使用生物化学、生理学和遗传学相结合的方法来(1)进一步定义PTP1B-/-小鼠瘦素超敏的原因、机制和后果；(2)确定PTP1B是否也调节下丘脑IR信号，如果是，则确定这种调节失去对PTP1B-/-鼠体质量表型的影响；以及(3)创建PTP1B的可诱导等位基因，并通过组织特异性基因敲除/重建策略，测试PTP1B在大脑和特定下丘脑区域的丢失对PTP1B-/体质量表型的贡献。建议的研究是由研究人员发起的与Barbara Kahn博士的互动研究项目Grant的一部分，该项目的重点是PTP1B在调节外周胰岛素活动中的作用。总之，我们的结果将对理解体重控制以及评估PTP1B作为肥胖症和/或2型糖尿病治疗靶点的有效性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.