LEPTIN INDUCED REVERSAL ON INSULIN RESISTANCE IN OBESITY

描述：(改编自申请者的摘要)骨骼肌抵抗 是导致高血糖、高胰岛素血症和血脂异常的主要因素 与II型糖尿病和肥胖症有关。最近的研究表明 瘦素，脂肪细胞衍生的激素，在改善胰岛素敏感性方面。因此， 瘦素缺陷ob/ob小鼠应用瘦素纠正高血糖和 高胰岛素血症，而正常大鼠升高瘦素会增加胰岛素 敏感度。基于这些观察，瘦素对代谢的影响 高脂喂养大鼠的异常，一种饮食诱导的肥胖模型 与单基因肥胖模型相比，更接近人类肥胖的是 调查过了。这些研究由P.I.执行，并在本文中讨论 建议，证明一种提高血浆水平的基因治疗干预 瘦素水平逆转骨骼肌胰岛素抵抗等 与饮食引起的肥胖相关的代谢异常。然而， 这些效应背后的机制尚不清楚。因此，这项提议， 重点是确定瘦素诱导逆转的机制 饮食诱导肥胖中骨骼肌胰岛素抵抗的研究。三个具体的 AIMS将通过以下方式测试骨骼肌胰岛素抵抗的假设 瘦素。这些变量与胰岛素的发病机制有关。 抵抗力和肌肉胰岛素敏感性的测定，并被改变 瘦素的作用。瘦素逆转作用机制的研究进展 肌肉胰岛素抵抗的研究可作为合理设计胰岛素抵抗的平台 药物或基因疗法治疗人类肥胖和胰岛素抵抗 II型糖尿病。 具体目标：1.确定脂代谢改变在 介导瘦素诱导的胰岛素敏感性的改善。2.确定 胰岛素信号转导通路活性改变在信号转导中的作用 瘦素可改善胰岛素敏感性。3.确定 代谢基因表达改变在介导瘦素诱导的胰岛素抵抗中的作用 胰岛素敏感性。

DESCRIPTION: (Adapted from the applicant's abstract) Skeletal muscle resistance is a major contributor to the hyperglycemia, hyperinsulinemia and dyslipidemia associated with type II diabetes and obesity. Recent work has implicated leptin, the adipocyte-derived hormone, in improving insulin sensitivity. Thus, leptin administration to leptin-deficient ob/ob mice corrects hyperglycemia and hyperinsulinemia, while elevating leptin in normal rats increases insulin sensitivity. Based on these observations the effects of leptin on the metabolic abnormalities of the high-fat fed rat, a model of diet-induced obesity that more closely resembles human obesity than monogenetic obesity models, were investigated. These studies, performed by the P.I. and discussed in this proposal, demonstrate that a gene therapy intervention that elevates plasma leptin levels reverses the skeletal muscle insulin resistance and other metabolic abnormalities associated with diet-induced obesity. However, the mechanisms underlying these effects are unknown. This proposal, therefore, focuses on identification of the mechanisms underlying leptin-induced reversal of skeletal muscle insulin resistance in diet-induced obesity. Three specific aims will test the hypotheses that skeletal muscle insulin resistance by leptin. These variables have been implicated in the pathogenesis of insulin resistance and the determination of muscle insulin sensitivity, and are altered by leptin. Identification of the mechanisms mediating leptin-induced reversal of muscle insulin resistance may serve as a platform for the rational design of pharmaceutical or genetic therapy of insulin resistance in human obesity and type II diabetes. Specific Aims: 1. To determine the role of altered lipid metabolism in mediating leptin-induced improvements in insulin sensitivity. 2. To determine the role of altered activity of the insulin signaling pathway in mediating leptin-induced improvements in insulin sensitivity. 3. To determine the role of altered metabolic gene expression in mediating leptin-induced improvements in insulin sensitivity.