INS and obesity due to melanocortin 4 receptor deficiency: Interestingly, we also observed that VSMC from obese insulin-resistant Zucker fa/fa rats also show higher levels of O2−, and that antioxidants prevent the multiple defects of the NO/cGMP/PKG pathway, whereas H2O2  reproduces these defects in VSMC from lean, insulin sensitive Zucker fa/+ rats [168]: these data support the pivotal role of oxidative stress in the reduced response to NO in this animal model of obesity and insulin resistance, and can explain the reduced endothelium-independent relaxation observed by some authors in these animals in vivo [169].