Extracellular Vesiclemediated Regulation of Metabolism

项目摘要/摘要 脂肪组织功能障碍是肥胖症和II型糖尿病代谢紊乱的首要原因， 使其成为药物干预的一个有希望的靶点。这种活跃的、能量感应的内分泌器官 分泌许多对全身新陈代谢有深远影响的因素，除了它在 隔离潜在有毒的脂类物种。通过串扰来维持脂肪组织的正常功能 在包括脂肪细胞、内皮细胞、免疫细胞和成纤维细胞在内的常驻组织细胞之间，这一过程 在肥胖的情况下会受到干扰。脂肪组织对营养压力的反应效率可以 意味着持续的全身代谢动态平衡或病理学之间的差异。我最近出版的 研究发现，脂肪组织中的细胞交换富含 信号蛋白、脂类，以及潜在的miRNAs。这些转移事件由内皮细胞到血管内皮细胞 脂肪细胞轴；然而，脂肪细胞也分泌被摄取的EV，但组织中的其他细胞如 巨噬细胞或壁细胞。此外，我们还发现，在禁食的能量应激下，内皮细胞 EV的分泌被增强，并定位于脂肪细胞。这项工作开辟了巨大的潜力， 发现这些细胞之间的新信号通路，可能会提供对 肥胖症营养应激下支持健康与不适应脂肪组织重塑的途径 或者禁食。初步数据表明，内皮细胞EVS支持脂肪细胞在 通过增加脂肪细胞糖酵解储备实现线粒体高能应激。此外，脂肪细胞EV的产生 在线粒体功能障碍的背景下被增强，我们预测这将调节全身新陈代谢。 因此，我假设在能量压力下，脂肪组织内皮细胞和脂肪细胞工作 通过EV的产生协同调节全身新陈代谢。第一个目标将测试 假设内皮细胞EVS重新编程脂肪细胞代谢以促进有效的适应 脂肪细胞对代谢应激的反应。目标2将评估能量应激刺激脂肪细胞 分泌能改变全身新陈代谢的电动汽车。一般的方法将利用体外细胞培养 技术以及最近产生的细胞特异性线粒体功能障碍或细胞特异性小鼠模型 抑制电动汽车的生产。这项提议将使我有机会接受新陈代谢追踪方面的培训 谢勒实验室高技能专家的技术、老鼠生理学和人体组织获取 整个德克萨斯大学西南部。这些目标的成功实现有可能开辟一个新的领域 破译EV介导的代谢调节信号通路的研究。

Project Summary/Abstract Adipose tissue dysfunction is at the forefront of metabolic disturbances in obesity and type II diabetes, making it a promising target for pharmacological intervention. This active, energy-sensing, endocrine organ secretes number of factors that have profound effects on systemic metabolism, in addition to its role in sequestering potentially toxic lipids species. Proper function of adipose tissue is maintained by cross-talk between resident tissue cells including adipocytes, endothelial cells, immune cells and fibroblasts, a process that is disrupted in the obese condition. The efficiency at which the adipose tissue responds to nutrient stresses can mean the difference between sustained whole-body metabolic homeostasis or pathology. My recently published work describes the finding that cells in adipose tissue exchange extracellular vesicles (EV) that are rich in signaling proteins, lipids, and, potentially miRNAs. These transfer events are dominated by an endothelial-to- adipocyte axis; however, adipocytes also secrete EVs that are taken up but other cells in the tissue such as macrophages or mural cells. Furthermore, we found that under the energetic stress of fasting, endothelial cell EV secretion is enhanced and targeted to adipocytes. This work has opened up vast potential for the discovery of novel signaling pathways between these cells that may provide an understanding of what pathways support healthy vs maladaptive adipose tissue remodeling under the nutrient stress of obesity or fasting. Preliminary data suggests that endothelial cell EVs support adipocyte ATP production during mitochondrial energetic stress by increasing adipocyte glycolytic reserve. Furthermore, adipocyte EV production is enhanced in the context of mitochondrial dysfunction, which we predict will regulate systemic metabolism. Thus, I hypothesize that under energetic stress, adipose tissue endothelial cells and adipocytes work synergistically through EV production to modulate whole body metabolism. The first Aim will test the hypothesis that endothelial cell EVs reprogram adipocyte metabolism to promote efficient adaptation of the adipocyte to metabolic stress. Aim 2 will evaluate the concept that energetic stress stimulates adipocytes to secrete EVs that alter systemic metabolism. The general approach will take advantage of both in vitro cell culture techniques as well as recently generated mouse models of cell-specific mitochondrial dysfunction or cell-specific suppression of EV production. This proposal will give me the opportunity to be trained in metabolic tracing techniques, mouse physiology, and human tissue acquisition by highly skilled specialists in the Scherer lab and throughout UT Southwestern. Successful completion of these aims has the potential to open a new area of research to decipher EV-mediated signaling pathways in metabolic regulation.