胰岛素抵抗是2型糖尿病、高血压、冠心病等疾病的“共同土壤”。肾素血管紧张素系统（RAS）不仅调节体液平衡，也影响代谢过程。血管紧张素1型受体(AT1R)阻断剂（ARB）能减少2型糖尿病的发生，提示阻断RAS系统可治疗胰岛素抵抗。本课题组在国际上首次报道了针对AT1R的降压疫苗，该疫苗能降低血压、改善动脉粥样硬化和糖尿病肾病。新的前期研究表明疫苗能改善瘦素缺失（ob/ob）小鼠的胰岛素抵抗，而对瘦素受体缺失（db/db）小鼠没有效果。基于瘦素受体激活对胰岛素抵抗有重要的调节作用，我们提出假说：AT1R疫苗偏向性调节AT1R功能，通过下游G蛋白和非G蛋白相关信号通路转激活瘦素受体，从而改善胰岛素抵抗。本研究将首次通过疫苗免疫这种全新方式治疗胰岛素抵抗，可改善病人的治疗依从性，同时探究疫苗对瘦素信号通路的影响，揭示AT1R转激活瘦素受体的机制，为AT1R疫苗的进一步临床应用奠定基础。

Insulin resistance is the common soil for type 2 diabetes mellitus, hypertension and atherosclerosis. The renin-angiotensin system (RAS) is indispensable in adjusting body fluid and blood pressure. It also participates in metabolic control. Clinical researches have proved that angiotensin II type 1 receptor（AT1R） blockers(ARBs) can eliminate the incidence of diabetes, indicating that they could be used to improve insulin resistance. We have developed a novel vaccine, ATRQβ-001 targeting the second extracellular loop of AT1R. Previous studies have showed that ATRQβ-001 vaccine efficiently reduces blood pressure, ameliorates atherosclerosis and diabetic nephropathy. We also found that this vaccine improves insulin resistance in leptin deficient but not leptin receptor deficient mice. Based on the fact that leptin and its receptor play important roles in mediating insulin resistance, we propose that as a biased AT1R regulator, ATRQβ-001 vaccine transactivates leptin receptor via G protein-dependent or G protein-independent signaling and ameliorates insulin resistance. This is the first time using a vaccine to treat insulin resistance and it enhances the poor compliance. We will investigate the impact that ATRQβ-001 vaccine makes on insulin resistance and leptin signaling, and clarify the mechanism for how the vaccine ameliorate insulin resistance. This study shows how the vaccine transactivates leptin receptor and lays foundation to its future clinical use.