In brief, this study provides a combined analysis of VAT proteome and ubiquitylome remodeling in HFD-induced obesity and discovers that HFD upregulates the ubiquitination level of six-transmembrane epithelial antigen of prostate 4 (STEAP4) in the VAT of DIO mice, leads to the degradation of STEAP4 via the ubiquitin-mediated proteasomal pathway, thereby causing a decrease in the protein level of STEAP4, which further results in reduced mitochondrial function in adipocytes. This evidence concerns the gene STEAP4 and obesity due to melanocortin 4 receptor deficiency.