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

摘要 II型糖尿病(T2D)的发展与肥胖密切相关，两者都是公认的危险因素 心血管疾病的致病因素。血管功能障碍是发生心血管疾病的早期事件 在肥胖糖尿病(OB-T2D)患者中。因此，我们制定了我们的长期目标，以确定 针对这些机制的血管功能障碍和纠正策略，如体力活动和体重 损失。我们最近发现，人类脂肪组织释放细胞外小泡(脂肪脂体)，这些小泡是 有效地被内皮细胞捕获。已知脂肪体能携带生物活性物质，如蛋白质和 MicroRNAs；然而，还没有研究它们的脂含量，也没有研究它们将其脂类货物转移到 内皮细胞。在目前的应用中，我们建议研究脂肪脂体在沟通中的作用。 在OB-T2D受试者中，不健康的环境，主要是调节失调的血脂，对血管内皮细胞有影响。在这些脂类之上 我们建议由脂肪脂体携带的物种是鞘糖脂(GSLS)。GSLS起源于 神经酰胺糖基化，一种在炎症和高血糖存在时上调的化学过程 级别。我们的初步研究结果表明，在内皮细胞中，富含GSL的脂质体干扰了质膜 结构，继而导致内皮功能障碍。此外，我们发现预适应内皮细胞 具有高剪切力的细胞(这是一种运动模拟物)保护内皮细胞免受有害影响 由脂肪脂体引起。因此，我们的中心假设是OB-T2D患者的脂肪组织释放 可导致血管内皮功能障碍的GSL脂质体。我们建议运动和减肥 干预措施(减肥手术)将恢复脂肪组织的动态平衡，减少GSL载脂体量，以及 随后降低OB-T2D患者的血管风险。我们将通过追求以下内容来验证我们的假设 目的：目的1：探讨富含GSL的脂质体在梗阻性黄斑变性血管内皮细胞功能障碍中的作用。 T2D成人；目标2：测试运动训练在减少脂肪体介导性高血压的有效性 血管功能；以及目标3：检查代谢性手术后脂肪/小凹轴线的变化。 它们与血管功能的关系。这项研究将提高我们对生物学机制的理解。 肥胖和T2D条件下脂肪小体的生产、包装和在诱发ED中的作用的基础。 它还将鉴定脂肪脂体及其与内皮细胞相互作用的拟议机制是新的 改善OB-T2D患者血管功能的治疗目标。一旦这些途径被阐明， 可以改进针对它们的策略，从而改进与T2D相关的治疗管理 心血管疾病。

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.