Role of PTP1B in Body Mass Regulation

PTP1B 在体重调节中的作用

• 批准号: 6909008
• 负责人: BENJAMIN G. NEEL
• 金额: $ 42.53万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909008
• 关键词: adipocytes; alleles; biological signal transduction; body composition; enzyme activity; gene targeting; genetically modified animals; glucose; homeostasis; hormone regulation /control mechanism; hypersensitivity; hypothalamus; insulin receptor; insulin sensitivity /resistance; laboratory mouse; leptin; noninsulin dependent diabetes mellitus; obesity; phenotype; phosphorylation; protein tyrosine phosphatase

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.

适当控制生物体的质量和组成对生存至关重要。 这一规则的障碍（例如，肥胖症）越来越常见，并且可能具有重要的医学后果，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/组成中起着关键作用。瘦素通过瘦素受体（LR）（一种I型细胞因子受体）传递信号，其通过激活相关的Janus家族激酶Jak 2和下游途径（包括Stat 3和Erk MAP激酶）来传递信号。 LR在关键的下丘脑核团上表达，所述核团通过神经肽的合成和分泌来调节食物摄入和能量消耗，以及在神经内分泌轴上表达，所述神经内分泌轴调节甲状腺激素、皮质类固醇和性类固醇的产生。 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，在那里它似乎具有anorectogenic/分解代谢作用。 蛋白酪氨酸磷酸酶（PTPs）也是酪氨酰磷酸化的关键调节因子，但特定PTPs在体重调节中的作用完全不清楚。 最近，发现缺乏PTP 1B的小鼠对胰岛素过敏，对饮食诱导的肥胖有抵抗力。 前者似乎是由于PTP 1B调节外周的IR，但PTP 1B-/-小鼠为什么瘦仍不清楚。我们的初步数据表明，PTP 1B-/-小鼠对瘦素过敏，可能对胰岛素的中枢神经系统作用过敏。 生化研究表明，PTP 1B可以直接将Jak 2去磷酸化。 我们假设PTP 1B负调节下丘脑LR和可能的IR信号，这种调节的丧失导致PTP 1B-/-小鼠的体重表型改变。 为了验证这一假设，我们将使用生物化学、生理学和遗传学相结合的方法来（1）进一步确定PTP 1B-/-小鼠中瘦素超敏性的原因、机制和后果;（2）确定PTP 1B是否也调节下丘脑IR信号传导，如果是，则这种调节丧失对PTP 1B-/-小鼠体重表型的后果;和（3）产生PTP 1B的可诱导等位基因，并通过组织特异性敲除/重建策略，测试脑和特异性下丘脑区域中PTP 1B的缺失对PTP 1B-/-体重表型的贡献。 拟议的研究是研究者发起的互动研究项目资助的一部分，Barbara Kahn博士的项目重点是PTP 1B在调节外周胰岛素作用中的作用。 总之，我们的研究结果将对理解体重控制以及评估PTP 1B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。