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. This evidence concerns the gene HIF1A and obesity due to melanocortin 4 receptor deficiency.