775-P: Mazdutide, a Dual GLP-1R/GCGR Agonist, Reduces Hyperuricemia by Modulating Energy and Lipid Metabolism and Inhibiting Hepatic Purine Metabolism

Introduction and Objective: Mazdutide (IBI362) is a dual agonist of GLP-1R and GCGR. Previous studies indicated that it significantly reduces serum uric acid levels in hyperuricemic rats compared to semaglutide. This study aims to further clarify the mechanism by which Mazdutide lowers uric acid in these rats. Methods: A hyperuricemia model was established in SD rats by administering adenine and potassium oxonate via gavage for 24 days following a 4-week high-fat diet starting at 8 weeks of age. After successful modeling, the rats were randomly divided into 8 groups. Following an 18-day intervention, we conducted single-nucleus RNA-Seq (snRNA-Seq) and metabolomic analyses. Results: SnRNA-Seq analysis shows that mazdutide increases GCGR expression in hepatocytes, while semaglutide slightly inhibits it. In hyperuricemic rats, fatty acid oxidation genes (Cpt1a, Fabp1, Apoa1, Acox1, Acaa1a) are significantly reduced, but mazdutide treatment markedly increases their expression. Conversely, Fatty acid synthesis genes (Acaca, Fasn) and glucose/purine metabolism genes (Pklr, G6pc1, Glul, Gckr, Gk, Nt5e, Ppat) are downregulated, Metabolomic analysis reveals that mazdutide lowers metabolites, including glucose, glucose-6-phosphate, L-glutamine, xanthosine, adenosine, uric acid and numerous other metabolites,consistent with control trends. Indicating a metabolic shift towards fatty acid oxidation and reduced production and utilization of purine precursors. Conclusion: Mazdutide significantly lowers serum uric acid levels in hyperuricemic rats by enhancing fatty acid oxidation and regulating energy metabolism in hepatocytes, ultimately reducing purine precursor production and utilization.Compared to Semaglutide, Mazdutide offers more substantial benefits in lowering uric acid levels. Disclosure Y. Ren: None. Y. Zhang: None. C. Liu: None. Z. Chen: None. X. Li: None. Y. Zhang: None. Y. Ma: None. X. Chen: None. H. Jiang: None. Funding Medical Science and Technology Research and Development Plan Major Project Jointly Constructed by the Henan Province and Ministerial Departments in China (No. SBGJ202301010)