Although numerous clinical trials have demonstrated a cardiovascular protective effect of SGLT2-i in patients with T2DM, the potential role and mechanisms of vascular alterations due to obesity are not fully understood, and analysis of aortic proteomics could provide valuable insights, so we investigated the alterations in the aorta of high-fat-induced obese mice and the efficacy of empagliflozin after administration. Here, SLC5A2 is linked to obesity due to melanocortin 4 receptor deficiency.