高脂是导致胰岛素抵抗为核心的代谢综合征的重要病理因素。近年研究认为高脂诱导的胰岛素抵抗与免疫失衡密切相关，项目组前期研究发现骨桥蛋白（OPN）在机体T细胞分化的免疫平衡调节中起关键作用，高脂喂养小鼠血浆OPN升高，内脏脂肪出现免疫紊乱，提示高脂与OPN升高和免疫紊乱有关，进一步研究发现小鼠脂肪自噬水平与胰岛素抵抗相关。但高脂如何引起免疫失衡和自噬导致胰岛素抵抗的作用机制目前仍不清楚。本课题拟选取用前脂肪细胞株，脂肪细胞和动物模型，利用共培养，基因敲除，抗体阻断，药物干预等手段，探讨高脂诱导脂肪组织OPN水平增高及自噬导致胰岛素抵抗的分子机制；明确高脂诱导免疫紊乱和自噬在胰岛素抵抗发生中的作用；最后在代谢综合征患者中验证干预高脂诱导胰岛素抵抗作用的关键分子和信号靶点改善胰岛素敏感性的作用。藉此为建立维持脂肪组织免疫稳态和避免自噬异常的胰岛素抵抗相关疾病的治疗新策略提供实验依据和理论基础。

High fat diet(HFD) is regarded as key pathology factor to metabolic syndrome centralized as Insulin resistance (IR). Recent research have proved that IR induced by HFD closely related to immune dysfunction. In previous studies, we have found that osteopontin(OPN) plays a key role in regulating differentiation of T cells in immune balance status. The serum level of osteopontin is discovered to increase obviously in HFD mice, the omental adipose tissue present to immune dysfunction. It suggests the internal relationship between HFD and OPN, immune dysfunction. Further study proved that there existed positive correlation between autophage level in adipose tissue of mice and IR. However, the functional mechanism on how HFD affects immune dysfunction and how autophage leads to IR remain to be further explored. .3T3-L1 cell line, primary adipocyte and animal model are planned to be selected in the project research by using the method of cells co-culture, gene knockdown, antibody blocking and drug intervention to investigate on the molecule Mechanism of elevating of OPN expression in adipose tissue induced by HFD and IR affected by autophage. Through the research we can make it more clear the HFD-leading immune dysfunction and autophage's functional role on Insulin resistance. Finally, our research team will testify the effectiveness on improving the Insulin sensitivity when intervening on key molecule originated from the process when HFD affects IR and moderating gene target in patients with metabolic syndrome.. Base on this research, we will present experimental evidence and academic framework basis by establishing a new therapy tactics on IR and its related disease by efforts on maintaining homeostasis of immune system and avoiding abnormal autophage in adipocyte.