Role of Adiposomes in Diabetes-Associated Endothelial Dysfunction and Restorative Effects of Exercise and Metabolic Surgery

脂肪体在糖尿病相关内皮功能障碍中的作用以及运动和代谢手术的恢复作用

• 批准号: 10532237
• 负责人: Abeer M Mohamed
• 金额: $ 74.39万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532237
• 关键词: Adipocytes; Adipose tissue; Adult; Aerobic Exercise; Affect; Biological; Biopsy; Blood Vessels; Body Weight decreased; Cardiovascular Diseases; Caveolae; Cell membrane; Cell surface; Cells; Ceramides; Characteristics; Chemicals; Communication; Cytoprotection; Data; Development; Diabetes Mellitus; Endothelial Cells; Endothelium; Event; Exercise; Glucose; Glycosphingolipids; Goals; Homeostasis; Human; Hyperglycemia; Hypoxia; In Vitro; Individual; Inflammation; Insulin Resistance; Lipids; Measures; Mediating; Mediator; Membrane; Metabolic; MicroRNAs; Molecular; NOS3 gene; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outcome; Pathogenesis; Pathway interactions; Patients; Permeability; Phosphorylation; Physical activity; Predisposing Factor; Process; Production; Property; Proteins; Randomized; Research; Risk; Role; Sampling; Signal Transduction; Structure; Surface; Testing; Therapeutic; Therapeutic Intervention; Thinness; Tissues; Vascular Diseases; Visceral; angiogenesis; arteriole; atherogenesis; bariatric surgery; cardiovascular risk factor; comorbidity; diabetic; effectiveness testing; endothelial dysfunction; exercise training; extracellular vesicles; glycosylation; improved; intercellular communication; lipid metabolism; mimetics; new therapeutic target; preconditioning; prevent; sensor; shear stress; social; src-Family Kinases; subcutaneous; synergism; transcytosis; uptake; vascular endothelial dysfunction; weight loss intervention

ABSTRACT The development of type II diabetes (T2D) is strongly associated with obesity, and both are well-established risk factors for cardiovascular disease. Vascular dysfunction is an early event in developing cardiovascular disease in obese diabetic (OB-T2D) patients. Therefore, we set our long-term goal to define molecular mechanisms of vascular dysfunction and corrective strategies that target these mechanisms, such as physical activity and weight loss. We recently discovered that human adipose tissues release extracellular vesicles (adiposomes) that are efficiently captured by endothelial cells. Adiposomes are known to carry bioactive cargos such as proteins and micro RNAs; however, their lipid content has not been studied, neither their ability to transfer their lipid cargo to endothelial cells. In the current application, we propose investigating the role of adiposomes in communicating the unhealthy milieu, mainly dysregulated lipids, to endothelial cells in OB-T2D subjects. On top of these lipid species that we propose to be carried by adiposomes are glycosphingolipids (GSLs). GSLs originate from ceramide glycosylation, a chemical process that is upregulated in the presence of inflammation and high glucose levels. Our preliminary findings showed that in endothelial cells, GSL-rich adiposomes disturb plasma membrane structure and subsequently induces endothelial dysfunction. Moreover, we found preconditioning endothelial cells with high shear stress (which is an exercise mimetic) protected endothelial cells from the detrimental effects caused by adiposomes. Therefore, our central hypothesis is that adipose tissues in OB-T2D patients release GSL-loaded adiposomes that induce vascular endothelial dysfunction. We propose that exercise and weight loss interventions (bariatric surgery) will restore adipose tissue homeostasis, reduce GSL-loaded adiposomes, and subsequently alleviate vascular risk in OB-T2D patients. We will test our hypotheses by pursuing the following Aims: Aim 1: Investigate the role of GSL-rich adiposomes in the pathogenesis of endothelial dysfunction in OB- T2D adults; Aim 2: Test the effectiveness of exercise training in reducing adiposome-mediated effects on vascular function; and Aim 3: Examine changes in adiposome/caveolae axis following metabolic surgery and their association with vascular function. This study will improve our mechanistic understanding of the biological underpinning of adiposome production, packaging, and role in inducing ED under conditions of obesity and T2D. It will also identify adiposomes and the proposed mechanisms of their interaction with endothelial cells as novel therapeutic targets for improving vascular function in OB-T2D individuals. Once these pathways are elucidated, strategies for targeting them can be advanced, leading to an improved therapeutic management of T2D-related cardiovascular disease.

抽象的 II型糖尿病（T2D）的发展与肥胖密切相关，两者都是公认的风险 心血管疾病的因素。血管功能障碍是发展心血管疾病的早期事件 在肥胖的糖尿病（OB-T2D）患者中。因此，我们设定了长期目标来定义分子机制 针对这些机制的血管功能障碍和纠正策略，例如体育锻炼和体重 损失。我们最近发现，人脂肪组织释放了细胞外囊泡（脂肪体） 有效地被内皮细胞捕获。已知脂肪小体携带生物活性千颗，例如蛋白质和 微RNA;但是，尚未研究它们的脂质含量，他们都不能将脂质货物转移到 内皮细胞。在当前的应用中，我们建议调查脂肪体在交流中的作用 在OB-T2D受试者中，不健康的环境（主要是失调的脂质）。在这些脂质上 我们建议由脂肪体携带的物种是糖磷脂（GSLS）。 GSL来自 神经酰胺糖基化，这种化学过程在炎症和高葡萄糖存在下被上调 水平。我们的初步发现表明，在内皮细胞中，富含GSL的脂质体干扰质膜 结构并随后引起内皮功能障碍。此外，我们发现了预处理内皮 具有高剪切应力的细胞（这是一种运动模仿）受保护的内皮细胞免受有害作用的影响 由脂质体引起。因此，我们的中心假设是OB-T2D患者的脂肪组织释放 诱导血管内皮功能障碍的GSL负载脂肪体。我们建议运动和减肥 干预措施（减肥手术）将恢复脂肪组织稳态，减少GSL负载的脂质体，并 随后减轻OB-T2D患者的血管风险。我们将通过追求以下内容来检验我们的假设 目的：目标1：研究富含GSL的脂肪体在OB-内皮功能障碍的发病机理中的作用 T2D成年人； AIM 2：测试运动训练在减少脂体介导的影响的有效性 血管功能； AIM 3：检查代谢手术后的脂质体/小窝轴的变化和 它们与血管功能的关联。这项研究将提高我们对生物学的机械理解 在肥胖和T2D条件下，脂质体产生，包装和在诱导ED中的作用的基础。 它还将识别脂质体和其与内皮细胞相互作用的提议的机制作为新颖 改善OB-T2D个体血管功能的治疗靶标。一旦阐明了这些途径， 可以提出针对目标的策略，从而改善与T2D相关的治疗管理 心血管疾病。