Overall, this study provides a putative mechanism by which CYP2B6 acts as an anti-obesity/anti-metabolic disease enzyme under HFD conditions and suggests how chemical inhibition or polymorphic loss of CYP2B6 activity could increase diet-induced obesity and metabolic disease through reduced production of important oxylipins or changes in circadian-mediated regulation of lipid metabolism and distribution. Here, CYP2B6 is linked to obesity due to melanocortin 4 receptor deficiency.