Here, we investigated the adipocyte specific Mir221 and Mir222 knockout (Mir221/222AdipoKO) mice fed with HFHS chow, and they were protected from the development of obesity by targeting DDIT4 (DNA damage inducible transcript 4)/TSC2 (tuberous sclerosis complex 2)/S6K (ribosomal protein S6 kinase) pathway. Here, DDIT4 is linked to obesity due to melanocortin 4 receptor deficiency.