777-P: The Dual Glucagon and Glucagon-Like Peptide 1 Receptor Agonist Mazdutide Outbalanced Glucagon-Like Peptide 1 Receptor Agonist Semaglutide Monotherapy in Improving Mice Liver Fat Accumulation

Introduction and Objective: This study aimed to explore the mechanism of the dual GCGR/GLP-1R agonist mazdutide for improving liver fat accumulation compared to the GLP-1R agonist semaglutide. Methods: Mazdutide (30 nmol/kg per week) or semaglutide (30 nmol/kg every other day) was administrated subcutaneously for 8 weeks in diet-induced obesity mice to maintain a comparable level of glycemic control. Parameters associated with body weight, hepatic fat accumulation, and transcriptomic results were analyzed. Results: Mazdutide treatment reduced body weight to a greater extent than semaglutide treatment (40.1% vs 28.1%, P < 0.001), with a lower fat mass percentage trend (11.2% vs 15.6%, P = 0.116). Lower serum TG (0.56 vs 0.80 mmol/L, P = 0.006), TC (2.85 vs 3.97 mmol/L, P < 0.001), and LDL-C (0.32 vs 0.62 mmol/L, P < 0.001) levels were shown in the mazdutide group, along with a reduction in liver TC level (0.05 vs 0.06 μmol/mg protein, P = 0.045). Liver H&E and Oil red O staining further confirmed the above results. Liver RNA-sequencing and KEGG enrichment analysis showed that mazdutide predominantly activated oxidative phosphorylation and fatty acid degradation pathways, and lipid metabolism-related genes such as Ehhadh, Cyp4a14, Hadha, Fgf21, and Gdf15 were upregulated, indicating that it facilitated fatty acid oxidation in the liver compared to semaglutide. We further screened differentially expressed transcription factors (TF) through the TRRUST database and found that activating transcription factor 3 (Atf3) upregulated in the mazdutide treatment group might be the functional TF regulating lipid degradation in the liver. Conclusion: The dual GCGR/GLP-1R agonist mazdutide exhibited a better efficacy in body weight loss and liver fat accumulation alleviation compared to the GLP-1R agonist semaglutide monotherapy potentially due to its promotion of fatty acid oxidation via ATF3. Disclosure Q. Wu: None. T. Wei: None. X. Cui: None. J. Yang: None. R. Wei: None. T. Hong: None. Funding the Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0506900, 2023ZD0507000); the National Natural Science Foundation of China (82170875); the Bethune Charitable Foundation (BFC-0XM-JC-20240607-01)