寒冷刺激调控MAIT细胞促进脂肪组织棕色化的作用及机制研究

白色脂肪棕色化障碍是驱动肥胖发生的重要因素之一，寒冷刺激是促进脂肪组织棕色化的经典调控因素，但具体机制尚未阐明。最新研究提示，脂肪组织内MAIT细胞比例与肥胖存在相关性。申请人前期研究发现，肥胖人群脂肪组织内MAIT细胞IL-4分泌能力下降，健康人群MAIT细胞与肥胖脂肪组织共培养可直接促进其棕色化的发生。动物实验则发现寒冷刺激可以增加脂肪组织IL-4+MAIT细胞，共培养实验中MAIT细胞促棕色化的效应可被IL-4抗体阻断。我们成功构建MAIT细胞缺陷小鼠MR1 KO小鼠，冷刺激后代谢率及脂肪棕色化水平均低于野生型小鼠。据此我们提出假设：寒冷刺激可以调控脂肪组织MAIT细胞分泌IL-4促进白色脂肪棕色化。本项目将基于现有的临床队列、基因敲除动物和流式细胞检测、组织共培养等技术，阐明MAIT细胞在脂肪组织白色脂肪棕色化中的作用，并揭示寒冷刺激调控脂肪棕色化的免疫新机制。

White fat browning disorder is one of the important factors driving obesity. Cold stimulation is a classic regulatory factor to promote fat browning, but the specific mechanism has not been clarified. Recent studies suggest that there is a correlation between the proportion of MAIT cells in adipose tissue and obesity. Previous studies of the applicant found that the IL-4 secretion ability of MAIT cells in adipose tissue of obese people decreased, and the co culture of MAIT cells and adipose tissue of healthy people can directly promote the occurrence of browning. In the co culture experiment, the browning effect of MAIT cells could be blocked by IL-4 antibody. We successfully constructed MAIT cell deficient MR1 KO mice, and the metabolic rate and fat browning water of cold stimulated offspring were lower than those of wild-type mice. Therefore, we hypothesized that cold stimulation could regulate the secretion of IL-4 by fat tissue MAIT cells and promote the browning of white fat. Based on the existing clinical cohort, gene knockout animals, flow cytometry and tissue co culture techniques, this project will clarify the role of MAIT cells in the browning of white adipose tissue, and reveal the new immune mechanism of cold stimulation regulating browning of adipose tissue.