By studying FBXW7 fat conditional transgenic and deficient mice, we demonstrated that FBXW7 promoted obesity and metabolic dysfunctions by targeting S6K1, a downstream effector of mTOR signaling, in thermogenic fat, which consequently impact preadipocyte proliferation via glycolytic product lactate. The gene discussed is RPS6KB1; the disease is obesity due to melanocortin 4 receptor deficiency.