Extracellular Vesiclemediated Regulation of Metabolism

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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.