遗传因素和饮食结构改变引起高同型半胱氨酸血症(HHcy)发病率提高,它与胰岛素抵抗相关。我们曾报道HHcy引起脂肪组织氧化应激和慢性炎症，其机制是引起内质网应激(ERS)损伤。已知抗炎和抗ERS的CGRP家族肽表达在疾病早期升高，晚期下降。本项目拟采用离体脂肪细胞与在体动物实验结合，借助本室已成功制备的CGRP家族多肽脂肪组织特异转基因或/和其受体修饰蛋白亚基敲除小鼠，给予HHcy或/和高脂喂养引起胰岛素抵抗，揭示(1)HHcy致脂肪细胞ERS损伤作用及CGRP家族多肽对其的拮抗作用机制；(2）CGRP家族多肽激活未折叠蛋白反应(UPR)，重建ER内稳态的分子机制；(3）哪种多肽及其受体修饰蛋白主要介导对脂肪细胞保护而维持脂肪细胞功能稳态；(4) CGRP家族多肽改善HHcy或/和高脂喂养引起的ERS损伤，继而减轻慢性炎症和脂肪功能紊乱及全身胰岛素抵抗，为筛选干预胰岛素抵抗提供新思路。

According to epidemiologic studies, homocysteine (Hcy) concentration was elevated in blood of insulin resistance and diabetic patients. To address that question, we have reported that Hcy promotes insulin resistance in mice through inducing ROS and chronic inflammation in adipose tissue via endoplasmic reticulum stress (ERS). As we have known that CGRP polypeptide superfamily possess anti-inflammation and anti-ERS effects in other tissue. They have shown to be released more in early stage and be reduced in the later stage of diseases. Therefore, we aimed to determine whether these peptides might protect against HHcy-induced ERS injury and inflammation as well as insulin resistance in adipose tissue, especially via alteration of ER chaperone function. We will use adipose tissue specific overexpression of CGRP superfamily peptide or receptor activity modifying protein knockdown mice with hyperhomocysteinmia or/and high fat diet treatment in the present study. The results will show that CGRP superfamily peptides directly affect on the adipose tissue, reverse Hcy-induced ERS injury and chronic inflammation, finally improving insulin sensitivity, which provides us a new strategy for the insulin resistance therapy.