Chronic treatment with glucagon-like peptide-1/glucagon receptor co-agonist causes weight-loss independent improvements in hepatic steatosis

Co-agonists at the glucagon-like peptide-1/glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Unlike GLP1, glucagon directly acts on the liver to reduce fat content. To date most metabolic studies have looked at heavily GLP1R-biased co-agonists and have not distinguished weight-loss versus weight loss-independent effects. We demonstrate that 24 days’ treatment with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, in mice with hepatic steatosis secondary to diet-induced obesity leads to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice: some known targets of glucagon signalling and others with as yet unclear physiological significance. Our study supports the development of GLP1/GCGR co-agonists for treatment of MASLD and related conditions. Mice with hepatic steatosis and Diet Induced Obesity were treated with vehicle, Dicretin (a GLP1/GCGR co-agonist), Semaglutide (GLP1R agonist), or equivalent weight loss by calorie restriction. Four samples from each treatment group were selected for NGS sequencing, followed by Gene Set Enrichment Analysis.