Metformin and 4-ME could significantly ameliorate the macrophage infiltration, collagen level, and HIF1α and TGF-β expression in the epididymal adipose tissue in HFD-fed mice, indicating the improvement of the epididymal adipose tissue microenvironment, thus counteracting the disorder of lipid metabolism in the liver caused by obesity. The gene discussed is TGFB1; the disease is obesity due to melanocortin 4 receptor deficiency.