1686-P: Dual GLP-1R/GCGR Activation Reprograms Systemic and Hepatic Metabolism to Ameliorate MAFLD

Introduction and Objective: MAFLD is a prevalent chronic liver disorder with limited pharmacological options. Mazdutide is a dual agonist of the glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) approved for diabetes and obesity. This study aimed to evaluate the therapeutic effects and mechanisms of mazdutide in a diet-induced obese (DIO) mouse model of MAFLD. Methods: DIO mice were treated for eight weeks with mazdutide, semaglutide, or vehicle. A pair-fed group matched the food intake of the mazdutide group. Body weight, body composition, energy expenditure, glucose tolerance, and insulin sensitivity were assessed. Liver histology and serum and hepatic biochemical parameters were analyzed. Transcriptomic, proteomic, and metabolomic analyses were performed to investigate molecular mechanisms. Results: At only one-third the dose of semaglutide, mazdutide achieved comparable glucose-lowering effects and more pronounced weight loss. It significantly reduced systemic fat mass, remodeled energy metabolism, and improved systemic glucose tolerance and insulin sensitivity. Histological analysis revealed its ability to alleviate hepatic lipid deposition, oxidative stress, and inflammatory responses. Pair-feeding experiments indicated that these benefits were not solely attributable to reduced food intake. Multi-omics analysis demonstrated that mazdutide reprogrammed hepatic lipid metabolism by suppressing lipid uptake, de novo lipogenesis, and lipid droplet formation, primarily through modulation of the PPAR signaling pathway. Conclusion: The dual GLP-1R/GCGR agonist mazdutide improves systemic metabolic homeostasis and liver pathology in experimental MAFLD. These data suggest that dual receptor activation confers metabolic benefits beyond single GLP-1R agonism, highlighting its potential therapeutic value for MAFLD. Disclosure D. Gao: None. Q. Pan: None. L. Guo: Consultant; Current; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Dreisamtech, Dongbao, Eli Lilly and Company, Gan & Lee Pharmaceuticals, Hansoh, Hengrui, Hua Medicine, Huadong Medicine, Innovent, Johnson & Johnson, Novartis AG, Novo Nordisk, Merck & Co., Inc., Pfizer Inc., Sanofi, Synapsor, Takeda Pharmaceutical Company Limited, Zense, 3sbio. Research Support; Current; Abbott Diabetes, AstraZeneca, Bayer AG, Dreisamtech, Eli Lilly and Company, Hansoh, Hengrui, Hua Medicine, Huadong Medicine, Innovent, Meitekanger, Novo Nordisk, Salubris, Sanofi, Synapsor, Zense. Funding Capital’s Funds for Health Improvement and Research(2022-1-4051), Beijing Municipal Science & Technology Commission (No Z221100007422007)