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: 10242234
• 负责人: Wei Ying
• 金额: $ 24.75万
• 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/10242234
• 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