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

脂肪组织巨噬细胞分泌外泌体-miR作为旁分泌/内分泌分子，直接调节胰岛素靶细胞功能以应对肥胖

• 批准号: 10475243
• 负责人: Wei Ying
• 金额: $ 24.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10475243
• 关键词: Adipocytes; Adipose tissue; Advisory Committees; Affect; Algorithmic Analysis; Animals; Attenuated; Beta Cell; Biological Assay; Biology; Bone Marrow; Cell physiology; Cells; Chronic; Computational algorithm; Data; Development; Diabetes Mellitus; Endocrine; Epidemic; Etiology; Event; Future; Genes; Genomics; Glucose; Glucose Intolerance; Goals; Hepatocyte; Homeostasis; Immunologics; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Resistance; Macrophage Activation; Measurement; Mediating; Mentors; Metabolic; Metabolic syndrome; Methods; MicroRNAs; Mus; Muscle Cells; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; PPAR gamma; Pathogenesis; Phenotype; Process; Regulation; Research; Role; Signal Transduction; Therapeutic; Thinness; Tissues; Training; Transplantation; Type 2 diabetic; basal insulin; base; cell type; diabetic patient; exosome; experimental study; gene network; glucose production; glucose tolerance; glucose transport; high risk; impaired glucose tolerance; improved; in vivo; insight; insulin sensitivity; insulin signaling; macrophage; new therapeutic target; obesity development; overexpression; paracrine; recruit; response

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.

项目摘要 肥胖现在是一种流行病，并已成为最常见的原因之一， 胰岛素抵抗胰岛素抵抗是糖尿病发病的关键病因， 代谢综合征代谢综合征的长期状态驱动 2型糖尿病的治疗这一过程中的一个重要事件是， 巨噬细胞向胰岛素靶组织的募集和激活。然而，在这方面， 巨噬细胞调节肿瘤发生的机制 肥胖引起的胰岛素抵抗还不完全清楚。肥胖驱使 脂肪组织巨噬细胞（ATM）对促炎性 表型，随后影响巨噬细胞与 脂肪细胞或其它胰岛素靶细胞。在这里，我们的目标是发现外泌体 miRNA介导的系统性胰岛素发病机制 灵敏度我的初步数据显示，自动取款机的不同激活信号， 可以递送到胰岛素靶点的外泌体miRNA的概况转换 细胞，并对这些细胞的胰岛素反应发挥深刻的调节作用。体内 结果表明，转移肥胖ATM分泌的外泌体损害葡萄糖 瘦WT受体小鼠的耐受性和胰岛素敏感性，而瘦ATM 外泌体显著减弱肥胖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泌体， 作为控制细胞胰岛素的旁分泌/内分泌分子的miRNAs 靶细胞的反应，最终介导全身胰岛素 灵敏度为了证明这一假设，我将1）调查 ATM衍生的外泌体miRNA对细胞胰岛素作用的影响; 2）研究ATM衍生的外泌体miRNA对细胞胰岛素作用的影响。 外泌体miR-155在调节胰岛素反应中的重要性; 3）确定 ATM-外泌体miRNAs调节细胞胰岛素的机制 应答这项研究将阐明ATM分泌的外泌体miRNA介导的 控制胰岛素敏感性的机制，最终目标是识别 胰岛素抵抗和2型糖尿病治疗的新靶点。