Exosomes and insulin action in metabolically healthy and unhealthy obesity

外泌体和胰岛素在代谢健康和不健康肥胖中的作用

• 批准号: 10721302
• 负责人: Samuel Klein
• 金额: $ 57.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10721302
• 关键词: Abdomen; Address; Adipocytes; Adipose tissue; Adverse effects; Biopsy Specimen; Blood Circulation; Blood specimen; Body Weight decreased; Body mass index; Cells; Ceramides; Diglycerides; FOXO1A gene; Foundations; Future; Gene Expression; Gene Proteins; Health; Hepatocyte; Heterogeneity; Human; IRS1 gene; Impairment; In Vitro; Insulin; Insulin Resistance; Lipids; Lipolysis; Liver; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; MicroRNAs; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Nuclease Protection Assays; Obese Mice; Obesity; Organ; PDPK1 gene; Participant; Pathway interactions; Persons; Phosphorylation; Plasma; Proteins; Proteomics; Technology; Therapeutic Intervention; Thinness; Western Blotting; body system; design; exosome; extracellular vesicles; glucose production; glucose tolerance; glucose uptake; in vivo; insight; insulin regulation; insulin sensitivity; insulin signaling; insulin tolerance; liquid chromatography mass spectrometry; new therapeutic target; non-alcoholic fatty liver disease; novel; obesity development; prevent; subcutaneous; therapeutic target; transcriptome sequencing; vesicular release

PROJECT SUMMARY Insulin resistance is commonly associated with obesity and is a major contributor to the development of obesity-related metabolic diseases, (e.g. nonalcoholic fatty liver disease [NAFLD] and type 2 diabetes). Most when characterized by glucose tolerance and insulin sensitivity. However, a subset of people with obesit adverse metabolic effects of excess adiposity. A better understanding of the mechanisms responsible for the differences in metabolic function between people with MHO and MUO can provide important mechanistic insights into the metabolic heterogeneity of obesity and possibly identify novel targets for therapeutic intervention. Small extracellular vesicles (sEVs, or exosomes) are produced by cells throughout the body and deliver bioactive molecules via the bloodstream to regulate metabolic processes in multiple organ systems. Studies in mice have found that sEVs released from adipose tissue modulate insulin sensitivity and contain regulatory miRNAs and bioactive lipids that alter insulin signaling. Consistent with these findings, we recently found that plasma and adipose tissue sEVs obtained from people with obesity and NAFLD impair insulin signaling in cultured myotubes, suggesting sEVs also contribute to the regulation of insulin sensitivity in people. In this proposal, we will evaluate the metabolic effects and cargo content of sEVs isolated from plasma and adipose tissue (AT) explant cultures obtained from three groups of participants. We will characterize participants based on adiposity and metabolic health: 1) metabolically healthy lean (MHL, BMI 18.5-24.9 kg/m2 and normal insulin sensitivity, defined as homeostatic model assessment of insulin resistance (HOMA-IR) <2); 2) metabolically healthy obese (MHO, BMI 30.0-44.9 kg/m2 and HOMA-IR<2); and 3) metabolically unhealthy obesity (MUO, BMI 30.0-44.9 kg/m2 and HOMA-IR>2.5). We posit that: i) sEVs from plasma and adipose tissue in people who are MUO have adverse effects on insulin action compared with sEVs from people who are MHL or MHO; ii) these metabolic differences are associated with differences in sEV content of miRNA and bioactive lipids; and iii) moderate 10% weight loss in people with MUO changes the miRNA and lipid content of plasma and adipose tissue sEVs and their effects on insulin action. The following specific aims will be addressed: 1) determine the effects of sEVs obtained from plasma and adipose tissue of MHL, MHO and MUO participants on: i) insulin action, gene expression and protein profile in cells vitro and in mice in vivo; 2) identify differences in miRNA and bioactive lipid profiles of plasma and adipose tissue sEVs obtained from MHL, MHO and MUO groups; and 3) determine whether a 10% weight loss-induced increase in insulin sensitivity in the MUO group will alter plasma and adipose tissue sEVs miRNA and lipid content and ameliorate the adverse effects of plasma and adipose tissue sEVs on insulin action in in vitro and in mice in vivo. These findings will provide the foundation for future studies in people designed to assess the potential of sEVs as a therapeutic target to prevent and treat the metabolic complications of obesity.

项目概要 胰岛素抵抗通常与肥胖有关，是导致肥胖的主要原因 肥胖相关的代谢疾病（例如非酒精性脂肪肝 [NAFLD] 和 2 型糖尿病）。最多 当以葡萄糖耐量和胰岛素为特征时 敏感性。然而，有一部分肥胖人群 过度肥胖对代谢产生不利影响。更好地理解负责的机制 MHO 和 MUO 患者代谢功能的差异可以提供重要的机制 深入了解肥胖的代谢异质性，并可能确定新的治疗靶点 干涉。 小细胞外囊泡（sEV 或外泌体）由全身细胞产生并输送 生物活性分子通过血液调节多个器官系统的代谢过程。研究于 小鼠发现从脂肪组织释放的 sEV 可调节胰岛素敏感性并包含调节性 改变胰岛素信号传导的 miRNA 和生物活性脂质。与这些发现一致，我们最近发现 从肥胖和 NAFLD 患者身上获得的血浆和脂肪组织 sEV 会损害胰岛素信号传导 培养的肌管表明 sEV 也有助于调节人的胰岛素敏感性。 在本提案中，我们将评估从血浆中分离出的 sEV 的代谢效应和货物含量，以及 从三组参与者获得的脂肪组织（AT）外植体培养物。我们将表征 基于肥胖和代谢健康的参与者：1）代谢健康的瘦肉（MHL，BMI 18.5-24.9 kg/m2 正常胰岛素敏感性，定义为胰岛素抵抗稳态模型评估 (HOMA-IR) <2)； 2）代谢健康的肥胖（MHO，BMI 30.0-44.9 kg/m2且HOMA-IR<2）； 3）新陈代谢不健康 肥胖（MUO、BMI 30.0-44.9 kg/m2 且 HOMA-IR>2.5）。我们假设： i) 来自血浆和脂肪的 sEV 与 MUO 患者的 sEV 相比，MUO 患者的组织对胰岛素作用有不利影响 是 MHL 或 MHO； ii) 这些代谢差异与 miRNA 的 sEV 含量差异相关， 生物活性脂质； iii) MUO 患者体重减轻 10% 会改变 miRNA 和脂质含量 血浆和脂肪组织 sEV 及其对胰岛素作用的影响。 将解决以下具体目标：1）确定从血浆和中获得的 sEV 的影响 MHL、MHO 和 MUO 参与者的脂肪组织：i) 胰岛素作用、基因表达和蛋白质谱 体外细胞和小鼠体内细胞； 2) 确定血浆和血浆中 miRNA 和生物活性脂质谱的差异 从 MHL、MHO 和 MUO 组获得的脂肪组织 sEV； 3）确定是否有10%的权重 MUO 组中胰岛素敏感性缺失引起的增加将改变血浆和脂肪组织 sEVs miRNA 和脂质含量，并改善血浆和脂肪组织 sEV 对胰岛素作用的不利影响 体外和小鼠体内。这些发现将为未来针对人类的研究奠定基础 评估 sEV 作为预防和治疗代谢并发症的治疗靶点的潜力 肥胖。