This study provides evidence that (i) obesity causes TNFα-dependent iNOS up-regulation, which increases basal NO production and contributes to impaired aortic function, and (ii) exercise training reduces TNFα/TNF-receptor/NF-κB signaling activation, which differently modulates the imbalance between eNOS and iNOS expression in the aorta under normal and high caloric intake. The gene discussed is TNF; the disease is obesity due to melanocortin 4 receptor deficiency.