NOS3 and obesity due to melanocortin 4 receptor deficiency: Acting via their cognate receptors insulin and insulin-like growth factor-1 (IGF-1) respond to environmental cues and nutrient availability to coordinate metabolism and growth.1 To do this, insulin and IGF-1 may act on multiple tissues, including the vascular endothelium where they activate endothelial nitric oxide synthase (eNOS) activation of the upstream kinase Akt.2 In aorta, we have shown that insulin and IGF-1 stimulated vasorelaxation and activation of eNOS is blunted in obesity.2