Adipose tissue macrophages secrete exosome-miRs as paracrine/endocrine molecules to directly modulate insulin target cell function in response to obesity

项目摘要 肥胖现在是一种流行病，已成为 胰岛素抵抗。胰岛素抵抗是糖尿病发病的主要病因。 代谢综合征。长期处于代谢综合征状态会导致 2型糖尿病的发展。这一过程中的一个重要事件是 巨噬细胞对胰岛素靶组织的募集和激活。然而， 巨噬细胞调控血管内皮细胞发育的机制 肥胖引起的胰岛素抵抗尚不完全清楚。肥胖的驱动因素 脂肪组织巨噬细胞(ATM)对促炎性反应的激活 表型，从而影响巨噬细胞与 脂肪细胞或其他胰岛素靶细胞。在这里，我们的目标是发现外体 MiRNA介导的全身性胰岛素发病机制 敏感度。我的初步数据显示，自动取款机的不同激活发出了信号 切换可传递到胰岛素靶点的外体miRNAs的特征 并对这些细胞的胰岛素反应进行深刻的调节。活体内 结果表明，转移肥胖的ATM分泌的外切体会损害葡萄糖 瘦WT受体小鼠在瘦ATM时的耐受性和胰岛素敏感性 外切体显著减轻肥胖WT受体小鼠的胰岛素抵抗。 因此，我认为脂肪组织巨噬细胞分泌外切体。 作为旁分泌/内分泌分子控制细胞胰岛素的miRNAs 靶细胞的反应，最终介导全身性胰岛素 敏感度。为了验证这一假设，我将1)调查 ATM来源的外体miRNAs对细胞胰岛素的作用；2)研究 外体miR-155在调节胰岛素反应中的重要性；3)确定 ATM-exosomal miRNAs调节细胞胰岛素的机制 回应。这项研究将阐明ATM分泌的外体miRNA介导的 控制胰岛素敏感性的机制，最终目标是确定 治疗胰岛素抵抗和2型糖尿病的新靶点。

Project abstract Obesity is now an epidemic and has become one of the most common causes of insulin resistance. Insulin resistance is the key etiology for the pathogenesis of metabolic syndrome. Prolonged status of metabolic syndrome drives the development of type 2 diabetes mellitus. An important event in this process is the recruitment and activation of macrophages to the insulin target tissues. However, the mechanisms whereby macrophages regulate the development of obesity-induced insulin resistance are not fully understood. Obesity drives the activation of adipose tissue macrophages (ATM) towards proinflammatory phenotype, which subsequently affects the interaction of macrophages with adipocytes or other insulin target cells. Here, we aim to discover exosomal miRNA-mediated mechanisms underlying the pathogenesis of systemic insulin sensitivity. My preliminary data show that the distinct activations of ATMs signal a switch in profile of exosomal miRNAs that can be delivered into the insulin target cells and exert profound regulation on insulin responses of these cells. In vivo results indicate that transferring obese ATM-secreted exosomes impair glucose tolerance and insulin sensitivity of lean WT recipient mice, while lean ATM exosomes remarkably attenuate insulin resistance of obese WT recipient mice. Therefore, I propose that adipose tissue macrophages secrete exosomal miRNAs as paracrine/endocrine molecules controlling cellular insulin responses of target cells, which eventually mediate systemic insulin sensitivity. To testify this hypothesis, I will 1) investigate the regulation of ATM-derived exosomal miRNAs on cellular insulin actions; 2) investigate the importance of exosomal miR-155 in regulating the insulin responses; 3) determine the mechanisms by which ATM-exosomal miRNAs regulate the cellular insulin responses. This research will elucidate ATM-secreted exosomal miRNA-mediated mechanisms controlling insulin sensitivity, with the ultimate goal of identifying novel targets for therapeutic treatment of insulin resistance and type 2 diabetes.