Rationale: Increasing prevalence of obesity and its associated risk with cardiovascular diseases demands a better understanding of the contribution of different cell types within this complex disease for developing new treatment options. Previous studies could prove a fundamental role of FTO (fat mass and obesity-associated protein) within obesity; however, its functional role within different cell types is less understood. Objectives: We identify endothelial FTO as a previously unknown central regulator of both obesity-induced metabolic and vascular alterations. Methods and Results: We generated endothelial Fto -deficient mice and analyzed the impact of obesity on those mice. While the loss of endothelial FTO did not influence the development of obesity and dyslipidemia, it protected mice from high-fat diet–induced glucose intolerance and insulin resistance by increasing AKT (protein kinase B) phosphorylation in endothelial cells and skeletal muscle. Furthermore, loss of endothelial FTO prevented the development of obesity-induced hypertension by preserving myogenic tone in resistance arteries. In Fto -deficient arteries, microarray analysis identified upregulation of L-Pgds with significant increases in prostaglandin D ₂ levels. Blockade of prostaglandin D ₂ synthesis inhibited the myogenic tone protection in resistance arteries of endothelial Fto -deficient mice on high-fat diet; conversely, direct addition of prostaglandin D ₂ rescued myogenic tone in high-fat diet–fed control mice. Myogenic tone was increased in obese human arteries with FTO inhibitors or prostaglandin D ₂ application. Conclusions: These data identify endothelial FTO as a previously unknown regulator in the development of obesity-induced metabolic and vascular changes, which is independent of its known function in regulation of obesity.