In summary, the current study demonstrated that HFD feeding led to the downregulation of AZGP1 expression in the hypothalamus, promoted the ubiquitination-mediated degradation of AGK and thus inactivated the downstream leptin-JAK2/STAT3-POMC signaling pathway, resulting in peripheral dysregulation of glucose/lipid metabolism and obesity-related phenotypes. This evidence concerns the gene AZGP1 and obesity due to melanocortin 4 receptor deficiency.