INS and obesity due to melanocortin 4 receptor deficiency: Integrated proteomic and untargeted metabolomic analyses of liver tissue were employed to decode mechanistic pathways, with key targets validated via molecular assays.<h4>Results</h4>Elevated dietary fat content dose-dependently accelerated obesity and T2DM onset, exacerbating glycolipid dysregulation, insulin resistance, hepatic steatosis, and adipose inflammation.