Increased circulating free fatty acids seen in obesity mediates endothelial dysfunction through several mechanisms including decreased tyrosine phosphorylation of IRS-1/2, impaired phosphorylation of eNOS via inhibition of the PI3K/Akt pathway, impaired ATP-induced mobilization, and influx of calcium in endothelial cells, increased ROS production via protein kinase C (PKC)-dependent activation of NADPH oxidase and consequent stimulation of inflammation via NF-κB activation [57,58,62]. The gene discussed is NOS3; the disease is obesity due to melanocortin 4 receptor deficiency.