For the first time, we demonstrated that sesamol could reduce body weight gain and improve obesity-associated metabolic disorders, which were dependent on the regulation of lipid metabolism in the liver, and the detailed mechanism was that sesamol down-regulated SREBP-1c and up-regulated p-HSL, PGC1α, and CPT1α in the liver. Here, PPARGC1A is linked to obesity due to melanocortin 4 receptor deficiency.