S100A8/A9--Myeloid cells特异性可溶性表氧化物水解酶(sEH)基因敲除改善胰岛素抵抗的新靶点

胰岛素抵抗是2型糖尿病的发病机制之一。脂肪组织巨噬细胞触发的炎症反应是胰岛素抵抗的始动因素之一。预实验结果提示可溶性表氧化物水解酶（soluble epoxide hydrolase, sEH）抑制剂TUPS显著抑制了高脂饮食诱导的胰岛素抵抗，其可能机制是通过降低模式动物血清中S100A8/A9的含量抑制脂肪组织巨噬细胞浸润与活化进而减轻炎症反应。因此，我们设想Myeloid cells特异性表达的sEH通过促进S100A8/A9表达调控巨噬细胞生成、招募、浸润与活化触发炎症反应引起胰岛素抵抗的发生与发展。本项目拟在胰岛素抵抗模式动物中，研究Myeloid cells特异性sEH基因敲除改善胰岛素抵抗的作用及其机制；探讨sEH基因敲除调控脂肪组织巨噬细胞招募、浸润与活化的作用机制。通过本项目研究阐明S100A8/A9是Myeloid cells特异性sEH基因敲除改善胰岛素抵抗的作用靶点。

Insulin resistance is one of the important pathogenesis of type 2 diabetes. Inflammatory response in adipose tissue triggered by macrophages is one of the initiating factors of insulin resistance. Our preliminary data demonstrated that soluble epoxide hydrolase inhibitor TUPS significantly improved insulin resistance induced by high-fat diet, which was associated with decreased local and systemic inflammatory response due to reduced macrophages infiltration and activation in adipose tissue mediated by the lower plasma S100A8/A9 level. Therefore, we hypothesize that sEH expressed in myeloid cells promotes S100A8/A9 synthesis and secretion, then triggers local and systemic inflammatory response by regulating myelogenesis, macrophages recruitment, infiltration and activation, which leads to insulin resistance. In this project, the effects and mechanisms of myeloid cells specific sEH gene knockout on insulin resistance in mice treated with high-fat diet will be explored. The potential effects of myeloid cells specific sEH gene knockout on myelogenesis, macrophages recruitment, infiltration and activation in adipose tissue will also be determined both in vivo and in vitro. Finally, S100A8/A9 will be identified as a new therapeutic target for myeloid cells specific sEH gene knockout to improve insulin resistance in this project.