Background: Mazdutide, a dual agonist of glucagon and GLP-1 receptor, has shown superior weight-loss effects compared to GLP-1R mono-agonists in the treatment of diabetes and obesity. This study aims to elucidate its unique mechanism of action.  
Methods: The 8-week-old db/db mouse model was used to compare the metabolic regulatory effects of Mazdutide and Semaglutide. Systematic monitoring of body weight, blood glucose, and food intake combined with ELISA and biochemical assays were used to evaluate glucose and lipid metabolism indexes. H&E staining, Oil Red O, and Bodipy staining were employed to analyze hepatic lipid accumulation and adipose tissue morphology. An energy metabolism monitoring system was used to assess energy expenditure, and RNA-Seq was performed to explore potential molecular mechanisms.
Results: Both Mazdutide and Semaglutide significantly reduced blood glucose and improved plasma insulin and glucagon levels in db/db mice from the perspective of glucose metabolism. However, Mazdutide led to more significant reductions in body weight and food intake compared to Semaglutide. Interestingly, in a pair-fed group (receiving the same amount of food as the Mazdutide group), weight loss was not significant, indicating that Mazdutide’s weight-reducing effects are not solely due to appetite suppression. In terms of lipid metabolism, Mazdutide also outperformed Semaglutide by reducing plasma and hepatic triglyceride and cholesterol levels, improving hepatic steatosis, and enhancing liver function of db/db mice. Histological analysis revealed that Mazdutide reduced white adipose droplet size and inhibited the "whitening" of brown adipose tissue. To investigate the mechanisms of the dual GLP-1R/GCGR agonist and the roles of GLP-1R and GCGR in obesity, we extracted the dataset (GSE211105) related to the dual GLP-1R/GCGR agonist and Semaglutide in epididymal adipose tissue of obese mice from the GEO database. The KEGG enrichment analysis showed that GLP-1R/GCGR dual agonist preferentially activated oxidative phosphorylation and upregulated energy metabolism. And We also found that Mazdutide significantly enhanced energy metabolism in db/db mice, whereas semaglutide had minimal effects in this reminima. These findings suggested that Mazdutide exerts a synergistic dual-receptor effect, promoting energy expenditure and improving lipid metabolism through unique mechanisms.
Conclusions: Mazdutide demonstrates a unique advantage in regulating energy metabolism through its dual receptor agonism. Its weight-loss mechanism involves the coordinated activation of energy metabolism networks across multiple organs, offering a new therapeutic strategy for metabolic diseases.  

Category:
Track 1: Metabolism and Integrative Physiology