巨噬细胞分泌miRs作为旁泌性分子介导脂肪细胞的炎症反应和胰岛素拮抗

Adipose tissue macrophage polarized activation exerts profound effects on the development of tissue inflammation and insulin resistance during obesity. However, it is unknown that adipose tissue macrophage secrets miRs as the paracrine molecule that directly modulates adipose tissue functions in response to obesity. In our in vitro study, the preliminary results showed that distinct polarized macrophages secret different miRs. In addition, these macrophage-secreted miRs can be carried by exosomes and delivered into adipocytes when co-culturing macrophages and adipocytes. Furthermore, adipocytes exhibited different responses after uptaking macrophage-secreted exosomes. In this study, using gene profiling and macrophage exosome-microRNA depletion mouse model, we will testify the hypothesis that adipose tissue macrophage controls adipocyte responses through paracrine-secreting miRs in the context of obesity. Our study will provide potential strategies to mitigate the pathogenesis of type 2 diabetes.

肥胖发展过程中，脂肪组织内巨噬细胞对于脂肪细胞的炎症反应和胰岛素拮抗发展具有重要的调控作用。巨噬细胞分泌的miRs是否参与介导靶脂肪细胞的功能反应，目前尚不清楚。本课题组前期体外细胞实验结果表明，不同极化状态的巨噬细胞分泌的miRs存在差异，并且对靶脂肪细胞的功能具有不同的诱导作用。本项目以巨噬细胞分泌miRs作为切入点，借助高通量基因测序和条件敲除巨噬细胞胞外体-miRs分泌小鼠模型等，明确脂肪组织内巨噬细胞是否通过分泌miRs作为旁泌性分子调控靶细胞的功能反应，从而阐明巨噬细胞介导脂肪细胞的炎症反应和胰岛素拮抗的作用机制。这将为预防和治疗2型糖尿病的发生发展提供可能的干预策略。

脂肪组织巨噬细胞对胰岛素拮抗发展具有重要的调控作用。本课题组研究发现巨噬细胞可以分泌外泌体/miRNAs作为旁泌性分子介导胰岛素敏感性。正常小鼠脂肪组织巨噬细胞分泌的外泌体有效提高靶细胞胰岛素敏感性，相反，肥胖小鼠脂肪细胞巨噬细胞的外泌体导致胰岛素拮抗。此外，肥胖诱导巨噬细胞外泌体内miRNAs成分发生显著变化，其中，miR-155显著富集于外泌体中。本课题组验证miR-155可显著降低靶基因PPARg水平，从而抑制靶细胞的胰岛素敏感性。抑制巨噬细胞外泌体分泌可有效降低肥胖诱导的胰岛素拮抗水平。以上研究成果揭示巨噬细胞分泌外泌体/miRNAs对机体胰岛素敏感性的调控作用，为未来应用外泌体/miRNAs作为靶目标以及研究肥胖代谢病和2型糖尿病诱发机制提供新的视角和开拓新的治疗手段。