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: 10230411
• 负责人: Wei Ying
• 金额: $ 24.9万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10230411
• 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; 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 肥胖现在已成为一种流行病，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会导致 2型糖尿病的发展。这个过程中的一个重要事件是 巨噬细胞募集和激活至胰岛素靶组织。然而， 巨噬细胞调节发育的机制 肥胖引起的胰岛素抵抗尚不完全清楚。肥胖驱动 脂肪组织巨噬细胞 (ATM) 的促炎激活 表型，随后影响巨噬细胞与 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泌体 全身胰岛素发病机制背后的 miRNA 介导机制 敏感性。我的初步数据显示，ATM 机的不同激活信号表明 外泌体 miRNA 谱的变化可递送至胰岛素靶点 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 分泌的外泌体会损害葡萄糖 瘦WT受体小鼠的耐受性和胰岛素敏感性，而瘦ATM 外泌体显着减弱肥胖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 miRNA 作为旁分泌/内分泌分子控制细胞胰岛素 靶细胞的反应，最终介导全身胰岛素 敏感性。为了证明这个假设，我将 1）研究 ATM 衍生的外泌体 miRNA 对细胞胰岛素作用的影响； 2）调查 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 miRNA 调节细胞胰岛素的机​​制 回应。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，最终目标是确定 胰岛素抵抗和 2 型糖尿病治疗的新靶点。