NOS3 and obesity due to melanocortin 4 receptor deficiency: This alternative pathway is especially important in oxidative environments, such as those associated with obesity, where endothelial dysfunction causes decreased eNOS activity due to factors like substrate (L-arginine) depletion, asymmetric dimethylarginine (ADMA) accumulation, and oxidative inactivation of tetrahydrobiopterin (BH4), a critical eNOS cofactor.