During the development of obesity and simultaneous insulin resistance, we have also demonstrated a similar decline in IGF-1 actions at a whole-body level5,16 and within the endothelium.5 While we have a deep understanding of the effects of whole-body and EC-specific insulin resistance on NO availability,6–9,17 the local and systemic consequences of prolonged insulin and IGF-1 resistance in the endothelium are unexplored. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.