高同型半胱氨酸血症引起脂肪组织内质网应激损伤与CGRP家族活性多肽的保护机制研究

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.

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。

遗传因素和饮食结构改变引起高同型半胱氨酸血症(HHcy)发病与脂肪胰岛素抵抗相关。我们还曾报道内源性抗炎和抗ERS的多肽CGRP家族肽在该疾病早期表达升高，晚期下降，但机制均不清楚。本项目针对以上问题进行了系列研究。揭示：(1)HHcy引起脂肪组织内质网内氧化还原调控变化介导了脂肪分解和脂肪肝发病增加及其机制；(2）HHcy也引起T淋巴细胞和巨噬细胞炎性激活的内质网-线粒体互作的代谢重塑机制；(3）HHcy/高脂饮食引起的脂肪组织慢性炎症和ERS损伤可以被多肽肾上腺髓质素2逆转；(4)主要机制是通过促进皮下白色脂肪米色化改善高脂饮食诱导的胰岛素抵抗。发表SCI文章共13篇，其中2篇综述，另外还发表一篇中文综述。 完成了计划研究内容和目标，取得了一些具有自主知识产权的研究结果。这些成果不仅使我们认识了发病新机制， 而且认识到内源性CGRP家族肽通过偏向激活其受体可能防治胰岛素抵抗和代谢性心血管疾病的新机制，为筛选干预代谢性相关疾病提供了新思路和新策略。