Angiocrine Control of Tissue Metabolism

Endothelial cells are important gatekeepers of organ homeostasis and metabolism. It has long been determined that impaired vascular function is associated with tissue dysregulation and metabolic disorders, but whether endothelial cells contribute to metabolic homeostasis beyond ensuring tissue perfusion is poorly described. Using an unbiased proteomics approach to analyze endothelial secretome, we identified GDF15 to be abundantly secreted. As GDF15 has been identified as an important modulator of metabolism through the control body weight, in this dissertation, the regulation of angiocrine GDF15 was explored and whether it influences other aspects of metabolism. It was determined that GDF15 expression is negatively controlled by FOXO1, master regulator of endothelial quiescence, but not NOTCH1, master regulator of endothelial specification. Inhibiting FOXO1 using the inhibitor AS1842856, increased GDF15 expression. In vivo, endothelial specific deletion of FOXO1 increased GDF15 expression (>4 fold) in endothelial cells isolated from different tissues and was associated with significant upregulation of GDF15 in urine and serum. Furthermore, endothelial specific deletion of FOXO1 provoked a significant decrease in food intake, suggesting that small changes in circulating GDF15 suffice to control food intake. Finally, it was determined that GDF15 has an acute insulin sensitizing effect, which is primary to the acute administration of GDF15 and independent of weight loss. This work identifies FOXO1 as a direct regulator of GDF15 in ECs and highlights the critical role of endothelial cells in whole body metabolic control