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.

项目摘要 胰岛素抵抗通常与肥胖有关，是导致发展的主要因素 肥胖相关的代谢疾病，例如非酒精性脂肪肝病[NAFLD]和2型糖尿病）。最多 当具有葡萄糖耐量和胰岛素的特征 灵敏度。但是，一部分肥胖者 过量肥胖的不良代谢作用。更好地理解负责的机制 MHO和MUO患者之间的代谢功能的差异可以提供重要的机制 对肥胖的代谢异质性的见解，并可能确定治疗性的新颖靶标 干涉。 细胞囊泡（Sevs或外泌体）由整个体内的细胞产生并提供 通过血液的生物活性分子调节多个器官系统中的代谢过程。研究 小鼠发现从脂肪组织释放的SEV会调节胰岛素敏感性并包含调节 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损害胰岛素信号传导的患者获得的血浆和脂肪组织SEV 培养的肌管，表明SEV也有助于调节人们的胰岛素敏感性。 在此提案中，我们将评估从等离子体和 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 和正常的胰岛素敏感性，定义为胰岛素抵抗（HOMA-IR）<2）的稳态模型评估； 2）代谢健康的肥胖（MHO，BMI 30.0-44.9 kg/m2和homa-ir <2）; 3）代谢不健康 肥胖（MUO，BMI 30.0-44.9 kg/m2和homa-ir> 2.5）。我们认为：i）来自等离子体和脂肪的Sevs 与来自MUO的人的组织对胰岛素作用有不利影响，而不是来自 是MHL或MHO； ii）这些代谢差异与miRNA和miRNA的SEV含量差异有关 生物活性脂质； iii）MUO患者中等10％的体重减轻，改变了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在 细胞体外和体内小鼠； 2）确定血浆和血浆生物活性脂质谱的差异和 从MHL，MHO和MUO组获得的脂肪组织SEV； 3）确定是否重量10％ MUO组损失引起的胰岛素敏感性的增加将改变血浆和脂肪组织SEVS MiRNA 以及脂质含量并改善等离子体和脂肪组织SEV对胰岛素作用的不利影响 体内小鼠的体外。这些发现将为未来研究的人提供基础 评估SEV作为预防和治疗代谢并发症的治疗靶标的潜力 肥胖。