Chronic treatment with glucagon-like peptide-1 and glucagon receptor co-agonist causes weight loss-independent improvements in hepatic steatosis in mice with diet-induced obesity - 16/06/24
Abstract |
Objectives |
Co-agonists at the glucagon-like peptide-1 and glucagon receptors (GLP1R/GCGR) show promise as treatments for metabolic dysfunction-associated steatotic liver disease (MASLD). Although most co-agonists to date have been heavily GLP1R-biased, glucagon directly acts on the liver to reduce fat content. The aims of this study were to investigate a GCGR-biased co-agonist as treatment for hepatic steatosis in mice.
Methods |
Mice with diet-induced obesity (DIO) were treated with Dicretin, a GLP1/GCGR co-agonist with high potency at the GCGR, Semaglutide (GLP1R monoagonist) or food restriction over 24 days, such that their weight loss was matched. Hepatic steatosis, glucose tolerance, hepatic transcriptomics, metabolomics and lipidomics at the end of the study were compared with Vehicle-treated mice.
Results |
Dicretin lead to superior reduction of hepatic lipid content when compared to Semaglutide or equivalent weight loss by calorie restriction. Markers of glucose tolerance and insulin resistance improved in all treatment groups. Hepatic transcriptomic and metabolomic profiling demonstrated many changes that were unique to Dicretin-treated mice. These include some known targets of glucagon signaling and others with as yet unclear physiological significance.
Conclusions |
Our study supports the development of GCGR-biased GLP1/GCGR co-agonists for treatment of MASLD and related conditions.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Highlights |
• | Dicretin is a dual agonist with 10-fold greater potency at GCGR than GLP1R. |
• | Unlike GLP1R monoagonism, Dicretin leads to weight loss-independent improvements in hepatic steatosis. |
• | Dicretin improves glucose tolerance comparably to weight loss by calorie restriction. |
• | Dicretin alters distinct hepatic metabolic pathways to those altered by weight loss or GLP1R agonism alone. |
Abbreviations : MASLD, DIO, GCGR, GLP1R, Sema, WM, HOMA-IR, HFD
Keywords : Metabolic dysfunction-associated steatotic liver disease (MASLD), non-alcoholic Fatty Liver Disease (NAFLD), weight loss, type 2 diabetes mellitus, glucagon, glucagon-like peptide-1
Plan
Vol 176
Article 116888- juillet 2024 Retour au numéro
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