From the Robert M. Berne Cardiovascular Research Center (N.K., L.A.B., M.E.G., C.A.R., A.G.W., L.J.D., S.M., E.H.M., V.S., A.K.B., N.L., S.K.S., B.E.I.), University of Virginia School of Medicine, Charlottesville.
Department of Molecular Physiology and Biophysics (L.A.B., V.S., S.K.S., B.E.I.), University of Virginia School of Medicine, Charlottesville.
Circ Res. 2020 Jan 17;126(2):232-242. doi: 10.1161/CIRCRESAHA.119.315531. Epub 2019 Dec 5.
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.
We identify endothelial FTO as a previously unknown central regulator of both obesity-induced metabolic and vascular alterations.
We generated endothelial -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 -deficient arteries, microarray analysis identified upregulation of with significant increases in prostaglandin D levels. Blockade of prostaglandin D synthesis inhibited the myogenic tone protection in resistance arteries of endothelial -deficient mice on high-fat diet; conversely, direct addition of prostaglandin D rescued myogenic tone in high-fat diet-fed control mice. Myogenic tone was increased in obese human arteries with FTO inhibitors or prostaglandin D application.
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.
肥胖及其相关心血管疾病风险的患病率不断增加，这就需要更好地了解在这种复杂疾病中不同细胞类型的作用，以开发新的治疗方法。之前的研究已经证明了 FTO（脂肪量和肥胖相关蛋白）在肥胖中的基本作用；然而，其在不同细胞类型中的功能作用还不太清楚。
我们确定内皮细胞中的 FTO 是肥胖引起的代谢和血管改变的一个以前未知的核心调节因子。
我们生成了内皮细胞缺陷型小鼠，并分析了肥胖对这些小鼠的影响。虽然内皮细胞 FTO 的缺失并不影响肥胖和血脂异常的发生，但它通过增加内皮细胞和骨骼肌中的 AKT（蛋白激酶 B）磷酸化，保护小鼠免受高脂肪饮食引起的葡萄糖不耐受和胰岛素抵抗。此外，内皮细胞 FTO 的缺失通过维持阻力动脉的肌源性张力，防止肥胖引起的高血压的发生。在 FTO 缺陷型动脉中，微阵列分析确定了的上调，其前列腺素 D 水平显著增加。在高脂肪饮食喂养的内皮细胞缺陷型小鼠中，阻断前列腺素 D 合成抑制了阻力动脉的肌源性张力保护；相反，直接添加前列腺素 D 挽救了高脂肪饮食喂养的对照小鼠的肌源性张力。肥胖患者的动脉中肌源性张力增加，可应用 FTO 抑制剂或前列腺素 D。
这些数据确定了内皮细胞 FTO 是肥胖引起的代谢和血管变化发展中的一个以前未知的调节因子，其作用独立于其在肥胖调节中的已知功能。
