Our findings ultimately support a model in which ANGPTL8 upregulated the expression of PPARγ and c/EBPα by inhibiting the Wnt/β-catenin signaling pathway and promoting the adipogenic differentiation of MSCs, resulting in lipid deposition in multiple organs and causing obesity in male mice. Here, ANGPTL8 is linked to obesity due to melanocortin 4 receptor deficiency.