Direct administration of 15-keto-PGE2, as well as genetic or pharmacological inhibition of PTGR2 (the enzyme responsible for degrading 15-keto-PGE2), prevented diet-induced obesity, improved glucose abnormalities, and reduced fatty liver without causing fluid retention or osteoporosis. Here, PTGR2 is linked to obesity due to melanocortin 4 receptor deficiency.