2型糖尿病(T2DM)的特征主要是胰岛素抵抗。表现为肥胖患者组织中脂肪过量堆积，机体存在持续炎症，进而损伤胰岛素靶组织及腺分泌组织的功能。NOD1为可识别脂肪酸等损伤因子的受体，其为胞质定位并可介导炎症发生。有研究表明脂代谢产物可改变肠系膜渗透性，加剧肠系菌群产物进入血液循环系统，NOD1敲除可以改善高脂饲喂导致的小鼠糖尿病，然而肥胖导致NOD1激活的分子机制尚未完全阐明。本项目组前期研究发现ZDHHC5对NOD1进行棕榈酰化修饰对于病原分子模式 (PAMPs) 激活NOD1依赖的免疫信号通路是必须的，因此推测PAMPs和脂代谢来源的危险信号分子均为T2DM病理进程的潜在重要因素。饱和脂肪酸通过促进NOD1的棕榈酰化，进而导致炎症发生，促进胰岛素抵抗。本项目拟阐明肥胖如何影响ZDHHC5调控NOD1棕榈酰化，并促进胰岛素抵抗相关的代谢性炎症反应。项目结果将为探寻糖尿病新的研究领域和治疗方法提供理想的药物靶点。

Type 2 diabetes is characterized by impaired response of the body’s tissues to insulin and impaired production of insulin from pancreatic beta cells. Obesity is associated with type 2 diabetes. In obesity, excess fat in tissues causes formation of damaging products that generate low-grade inflammation. Such inflammation in tissues that respond to insulin and tissues that produce insulin impairs their function, thus causing diabetes. However, antiinflammatory treatment of diabetes has been only partially effective so far, we believe because it is not.targeted towards the sensors of the fat-derived toxic products that initiate such low-grade inflammation. NOD1 is a sensor candidate because it is located inside cells and induces low-grade inflammation. Indeed, it has been shown that NOD1 deficiency protects against high fat diet-induced diabetes in mice. However, it is not known whether NOD1 is activated by fat-derived products or by bacterial products, since high fat diet can increase intestinal absorption of bacterial products. Recently, we have shown that NOD1 is palmitoylated by the PAT ZDHHC5 and this PTMs is important for PGN triggered NOD1 dependant signalling. Our HYPOTHESIS is that both PAMPs and fat-derived DAMPs are important factors in the pathogenesis of obesity-associated diabetes and act through NOD1/ZDHHC5 axis Consequently, the saturated fatty acid will promote palmitoylation of the NOD1 PRR by the ZDHHC5, and its palmitoylation is needed for the pro-inflammatory effects of both PAMPs.and fat-derived DAMPs, which brings about low-grade inflammation resulting in diabetes. Herein, we propose to study how high fat diet affects ZDHHC5 mediated NOD1 palmitoylation and this molecular mechanism promote metabolic and inflammatory alterations associated with insulin resistance.