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. The gene discussed is JAK2; the disease is Obesity.