(PTFS05-02-26) Effects of Two Glucagon-Like Peptide-1 Receptor Agonists (Semaglutide and Tirzepatide) on Metabolic Dysfunction-Associated Steatotic Liver Disease in Male and Female Mice

Objectives: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) affects ~25% of the global population and can progress to Metabolic Dysfunction-Associated Steatohepatitis (MASH). Weight loss of 5-10% is the only recommended approach for managing MASLD, with no currently approved targeted treatments. Anti-obesity and anti-diabetic Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) have also improved MASLD in some human studies. Our objective was to determine whether the mechanism(s) underpinning these improvements are attributable to weight loss, or activation of GLP-1R-dependent molecular pathways.

Methods: Diets had low methionine and choline deficiency, which rapidly induces fatty liver. Male (n = 10) and female (n = 10) C57BL/6J (B6) mice were divided into 4 groups varying in dietary fat and GLP-1RA administration; Low-fat (LF), High-fat (HF), HF + Semaglutide (SEM), and HF + Tirzepatide (TIR).  HF mice were fed for 8 weeks before respective GLP-1RA administration for 4 additional weeks (12 weeks total). Body weight was measured throughout the study, body composition was measured at week 11 (Echo-MRI), then livers (gene and protein expression and histology) and blood (serum hormone and cytokine analyses) were collected at termination for further analyses.

Results: SEM (P = .0008) and TIR (P = .0133) reduced body weight compared to HF in males but not females. Unexpectedly, Echo-MRI revealed that in males the HF group had significantly reduced fat mass compared to LF males (P < .0001), with no change females. However, SEM treatment reduced lean mass compared to HF in both males (P = .0298) and females (P = .0130). Liver gene expression analysis revealed improvements in markers of fatty acid oxidation: SEM increased Cpt1a in males (P = .0235), while TIR increased Pparα in females (P = .0103). Moreover, TIR reduced Tgf-β1 mRNA (marker of fibrosis) in males (P = .0015). Liver histology, protein, and serum analyses are ongoing.

Conclusions: While GLP-1RAs appear to reduce MASLD with discordant effects of SEM vs TIR, it remains unclear whether this is a direct or weight loss-related mechanism in male mice. Ongoing work in this study will incorporate additional multi-omics approaches to elucidate underlying mechanisms.

Funding Sources: Qatar National Research Fund (Qatar Foundation and Hamad Bin Khalifa University award # SARA-HBKU-ARG01-0521-230245#TTU)