Previous work has shown that in rodent models of diet-induced obesity, vascular insulin resistance (measured as decreased insulin-stimulated Akt and eNOS phosphorylation) is necessary and sufficient for, and thus precedes, the subsequent development of organ-specific and systemic insulin resistance (Kim et al. 2008; Kubota et al. 2011). Here, NOS3 is linked to obesity due to melanocortin 4 receptor deficiency.