Loss of endothelial Fto is protective against metabolic disease

Genetic variations within the fat mass and obesity associated gene (FTO) are known to correlate with obesity and hypertension in humans, demonstrating a possible key role in vascular health. Therefore, we hypothesized that FTO may be important at the vascular level. Because endothelial cells (EC) are known to have a central role in the development of obesity‐induced metabolic changes and hypertension, we wanted to investigate if murine loss of endothelial Fto may influence obesity‐induced pathophysiological changes. Therefore, EC‐specific Fto deficient mice were generated using a tamoxifen‐inducible Cre system. To analyze obesity‐dependent effects, mice were either fed a normal chow (NC) or a high fat diet (HFD) for 12 weeks. Regardless of the endothelial deletion of Fto , the mice still gained a significant amount of weight and were obese, indicating the Fto gene in endothelium did not inhibit weight gain like global Fto deficiency in mice. Next we determined whether loss of endothelial Fto affected obesity‐induced metabolic changes in HFD‐fed mice. While serum lipid analysis showed no differences in dependence of endothelial Fto, glucose and insulin tolerance was significantly improved in HFD‐fed mice without endothelial Fto. Due to the importance of EC in vascular tone of resistance arteries, we isolated 3 rd order mesenteric arteries from NC‐ and HFD‐fed mice with and without endothelial Fto and performed pressure curves to analyze myogenic tone. While loss of endothelial Fto did not influence myogenic tone in resistance arteries of NC‐fed mice, remarkably, endothelial Fto deletion provided protection from HFD‐induced changes on myogenic tone. Subsequently, blood pressure was measured in HFD‐fed mice with and without endothelial Fto using radiotelemetry and it revealed that loss of endothelial Fto significantly reduced blood pressure. Collectively, these data suggest that loss of endothelial Fto was protective against HFD‐induced changes on myogenic tone in mesenteric arteries and subsequently reduced blood pressure in vivo without influencing body weight. Furthermore, glucose homeostasis, but not serum lipid levels, were specifically improved in HFD‐fed mice suggesting that endothelial Fto is not only important in the development of obesity‐induced hypertension, but also in the development of insulin resistance and hyperglycemia. Support or Funding Information AHA, NHLBI and IRTG1902