LEPTIN INDUCED REVERSAL ON INSULIN RESISTANCE IN OBESITY

描述：（改编自申请人摘要）骨骼肌阻力 是高血糖、高胰岛素血症和血脂异常的主要原因 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。因此，在本发明中， 给予瘦素缺陷型ob/ob小鼠瘦素可纠正高血糖症， 高胰岛素血症，而在正常大鼠中升高瘦素会增加胰岛素 灵敏度基于这些观察结果，研究了瘦素对代谢的影响。 高脂喂养大鼠的异常，高脂喂养大鼠是饮食诱导的肥胖模型， 与单基因肥胖模型相比， 研究了这些研究由P.I.和讨论 该提案表明，基因治疗干预，提高血浆 瘦素水平逆转骨骼肌胰岛素抵抗和其他 与饮食引起的肥胖相关的代谢异常。但 这些影响的机制尚不清楚。因此，这项建议， 重点是确定瘦素诱导逆转的机制 骨骼肌胰岛素抵抗在饮食诱导肥胖中的作用。三个具体 目的是检验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 抵抗和肌肉胰岛素敏感性的测定，并改变 瘦素。瘦素诱导逆转的机制研究 肌肉胰岛素抵抗可能作为一个平台，为合理设计， 人肥胖症中胰岛素抵抗的药物或基因治疗， II型糖尿病 具体目标：1。为了确定脂质代谢改变在 介导瘦素诱导的胰岛素敏感性的改善。2.以确定 胰岛素信号通路的活性改变在介导 瘦素诱导的胰岛素敏感性改善。3.确定的作用 改变代谢基因表达介导瘦素诱导的改善， 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.