运动对小鼠肌肉组织miR-200b表达的影响及其改善胰岛素抵抗的分子机制研究

项目名称： 运动对小鼠肌肉组织miR-200b表达的影响及其改善胰岛素抵抗的分子机制研究

项目编号： No.81501954

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 李海燕

作者单位： 温州医科大学

项目金额： 17万元

中文摘要： 运动可以激活AMPK信号通路而改善胰岛素抵抗（IR），但其机制未完全阐明。已发现多种miRNAs在IR形成中发挥重要作用。最近发现， miR-200可抑制FOG2表达，降低其与PI3K蛋白结合，从而缓解IR。我们在前期研究中发现，在高脂诱导的IR小鼠模型肌肉组织中，miR-200b表达显著下降，而运动却可以提高其表达水平，并且在细胞水平上发现，AMPK可以调控miR-200b的表达。因此，我们推测运动通过激活AMPK升高miR-200b的表达，进而抑制FOG2，而起到改善IR的作用。另外，我们在已经构建的miR-200b转基因小鼠肌肉组织中发现IKKβ和IRAK4表达显著降低，提示miR-200b也可能对抑制NF-kB信号通路活性，减轻炎症反应，而改善IR。本课题拟通过长期运动来干预IR小鼠模型，研究miR-200b是否可以通过上述机制在运动改善胰岛素抵抗中发挥作用，及其与AMPK的关系。

中文关键词： 运动；miR-200；胰岛素抵抗；骨骼肌；AMP依赖的蛋白激酶

英文摘要： Exercise could improve insulin resistance through activating AMPK signal pathway; however, the underlying mechanism remains unclear. It has been proved that a variety of miRNAs played important roles in the development of insulin resistance. Recently, miR-200b, a microRNA involved in the epithelial to mesenchymal transition (EMT), has been found that it could inhibit the expression of FOG2, which could bind to PI3K to form a complex and reduce the activity of insulin pathway. In the previous work, we have found that miR-200b was significantly reduced in the skeleton muscles in the high fat diet induced mice with insulin resistance, whereas the exercise could increase the expression of miR-200b in the HFD mice. Furthermore, it was indicated that miR-200b was regulated by AMPK through the cellular experiment. We hypothesized that AMPK could up-regulate the expression of miR-200b, subsequently repress the expression of FOG2, and improve insulin resistance during exercise. Moreover, we also found that the key molecules in the NF-kB pathway, IKKβ and IRAK4, significantly reduced in the skeleton muscles of miR-200b transgenic mice, which suggested that miR-200b might repress the activity of NF-kB and alleviate inflammation induced by high fat diet so that improve insulin resistance. In this proposal, the mouse model with insulin resistance will be established and intervened by long term exercise, to investigate whether insulin resistance would be improved through the mentioned pathways regulated by miR-200b and its relationship with AMPK.

英文关键词： exercise;miR-200;insulin resistance;skeletal muscle;AMP activated protein kinase