Extracellular Vesiclemediated Regulation of Metabolism

项目总结/摘要 脂肪组织功能障碍是肥胖和II型糖尿病代谢紊乱的最前沿， 使其成为药理学干预的有希望的靶点。这个活跃的，感知能量的内分泌器官 分泌许多对全身代谢有深远影响的因子，除了其在 隔离潜在的有毒脂质物质。脂肪组织的正常功能是由串扰维持的 包括脂肪细胞、内皮细胞、免疫细胞和成纤维细胞在内的固有组织细胞之间的相互作用， 在肥胖状态下被破坏了。脂肪组织对营养应激的反应效率可以 是指持续的全身代谢稳态或病理之间的差异。我最近出版的 这项工作描述了脂肪组织中的细胞交换细胞外囊泡（EV）的发现， 信号蛋白、脂质和潜在的miRNA。这些转移事件由内皮细胞- 然而，脂肪细胞也分泌EV，这些EV被吸收，但组织中的其他细胞， 巨噬细胞或壁细胞。此外，我们发现，在禁食的能量应激下，内皮细胞 EV分泌增强并针对脂肪细胞。这一工作为 这些细胞之间新的信号通路的发现，可能提供了一个什么样的理解 途径支持肥胖营养应激下健康与适应不良的脂肪组织重塑 或者禁食初步数据表明，内皮细胞EV支持脂肪细胞ATP的产生， 线粒体能量应激通过增加脂肪细胞糖酵解储备。此外，脂肪细胞EV产生 在线粒体功能障碍的情况下增强，我们预测这将调节全身代谢。 因此，我假设在能量应激下，脂肪组织内皮细胞和脂肪细胞工作 通过EV产生协同调节全身代谢。第一个目标将测试 假设内皮细胞EV重编程脂肪细胞代谢以促进 脂肪细胞对代谢应激的反应。目的2将评估能量应激刺激脂肪细胞 分泌改变全身代谢的EV。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线粒体功能障碍的小鼠模型。 抑制EV生产。这个提议将给我机会接受代谢追踪方面的培训 技术，小鼠生理学和人体组织采集由谢勒实验室的高技能专家和 整个UT西南部成功地完成这些目标有可能开辟一个新的领域， 研究以破译EV介导的代谢调节信号通路。

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.