脂肪组织巨噬细胞极化在EETs改善胰岛素抵抗中的作用

项目名称： 脂肪组织巨噬细胞极化在EETs改善胰岛素抵抗中的作用

项目编号： No.81471021

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 徐西振

作者单位： 华中科技大学

项目金额： 75万元

中文摘要： 巨噬细胞诱导的脂肪组织炎症是肥胖相关胰岛素抵抗的发病机制之一，抑制脂肪组织巨噬细胞诱导的炎症是治疗胰岛素抵抗的一个新靶点。花生四烯酸细胞色素P450表氧化酶2J3过表达显著改善了模式动物的胰岛素抵抗，因此设想EETs通过抑制脂肪组织巨噬细胞诱导的炎症改善胰岛素抵抗。本项目拟在高脂饮食诱导的小鼠与db/db 2型糖尿病小鼠胰岛素抵抗模型中，研究直接微量泵入EETs改善上述两种模式动物胰岛素抵抗的作用及其抗炎症机制；研究EETs与sEH抑制剂1471抑制胰岛素抵抗模式动物脂肪组织炎症的效应及其机制；并在细胞水平上，研究EETs与1471抑制巨噬细胞招募、浸润、活化与局部增殖和促进其向M2巨噬细胞极化的作用及其机制。另外，深入研究myeloid细胞CYP2C44特异性敲除对高脂饮食诱导的胰岛素抵抗的影响及其机制。通过本项目研究将进一步阐明EETs防治胰岛素抵抗的作用及其机制。

中文关键词： 环氧-二十碳-三烯酸；胰岛素抵抗；巨噬细胞极化；脂肪组织；炎症

英文摘要： Adipose tissue macrophage induced inflammation is one of the pathogenesis of obesity-related insulin resistance. Inhibiting adipose tissue inflammation induced by macrophages is a new target of insulin resistance prevention and treatment. Arachidonic acid Cytochrome P450 epoxygenase 2J3 overexpression significantly improved insulin resistance in rats treated with fructose and db/db diabetic mice. It is hypothesized that EETs improve insulin resistance by inhibiting macrophage-induced adipose tissue inflammation. In this project, the roles and mechanisms of EETs infusion by minipump on insulin resistance will be investigated in C57BL/6J mice treated with high-fat diet and db/db diabetic mice, and moreover, the effects and mechanisms of EETs or soluble epoxide hydrolase inhibitor 1471 on adipose tissue inflammation will be explored in C57BL/6J mice treated with high-fat diet and db/db diabetic mice. In addition, the effects and mechanisms of EETs or 1471 on macrophage recruitment, infiltration, activation and local proliferation as well as macrophage polarization will be studied in vitro and ex vivo. Importantly, the impacts and mechanisms of myeloid cells specific CYP2C44 deficiency on insulin resistance induced by high fat diet will be explored. The beneficial roles of EETs on the prevention and treatment of insulin resistance will be further identified in this project.

英文关键词： EETs;Insulin resistance;Macrophage polarization;Adipose tissue;Inflammation