Distinct Effects of Semaglutide and Tirzepatide on Metabolic and Inflammatory Gene Expression in Brown Adipose Tissue of Mice Fed a High-Fat, High-Fructose Diet

Tianyi Ma^1,2,3Fanfan Song^2,3,4Yongning Pan^2,3,5Ying He^1,2,3Xinming Cao^2,3,5Yan Zhang^1,2,3Guangyao Song^2,3*Luping Ren^2,3*

• ¹Graduate School of Hebei Medical University, Shijiazhuang, China
• ²Hebei General Hospital, Shijiazhuang, China
• ³Hebei Key Laboratory of Metabolic Diseases, shijiazhuang, China
• ⁴North China University of Science and Technology School of Clinical Medicine, Tangshan, China
• ⁵Hebei North University School of Graduate Studies, Zhangjiakou, China

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 randomized into either a control group (CON; n=7, standard diet) or an obesity model group (n=21, HFHFD). Following the establishment of obesity, the obese mice were further randomized into three intervention groups (n=7) and administered subcutaneous injections of saline, semaglutide, or tirzepatide for 7 weeks. Metabolic parameters (including body weight, glycemic and lipid profiles, and insulin levels) and BAT This is a provisional file, not the final typeset article morphology were assessed. RNA sequencing of BAT was conducted to identify differentially expressed genes (DEGs), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) analyses. Reverse Transcription Quantitative Polymerase Chain Reaction (RT-qPCR) was subsequently employed to validate the expression of selected DEGs. 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, 268 upregulated), whereas tirzepatide modulated 40 genes (20 downregulated, 20 upregulated). Bioinformatic analysis identified Cyp1a1, Hsd11b1, Atp1a3, Tfrc, Ptger4, and Il1b as potential therapeutic targets. Conclusion: Semaglutide and tirzepatide may share common targets (Cyp1a1, Hsd11b1, Atp1a3) that enhance insulin sensitivity, improve metabolism, and promote weight loss. Tfrc, Ptger4, and Il1b may also serve as tirzepatide-specific targets, potentially elucidating its enhanced anti-inflammatory and metabolic regulatory effects.