BACKGROUND: Brown adipose tissue (BAT) is crucial for overall energy homeostasis as a thermogenic organ with high metabolic activity. While the recruitment of BAT contributes to improved glycemic and lipid homeostasis, the exact molecular mechanisms remain incompletely understood. OBJECTIVE: This investigation compared the transcriptomic responses of semaglutide (GLP-1 receptor agonist) and tirzepatide (dual GIP/GLP-1 receptor agonist) on BAT in mice fed a high-fat, high-fructose diet (HFHFD). These outcomes enhance our understanding of the metabolic actions of GLP-1 and dual GIP/GLP-1 receptor agonists, providing a conceptual basis for future BAT-targeted therapeutic strategies. METHODS: Twenty-eight male C57BL/6J mice were randomly assigned to either a control group (CON; RESULTS: Both semaglutide and tirzepatide reduced body weight, improved lipid profiles, and enhanced insulin sensitivity. Compared with the saline group, administration of semaglutide led to differential expression of 467 genes (199 downregulated and 268 upregulated), whereas tirzepatide modulated 40 genes (20 downregulated and 20 upregulated). Bioinformatic analysis identified CONCLUSION: Semaglutide and tirzepatide may share common targets (