Multiparametric MRI Evaluation of Liver Fat and Iron after Glucagon-like Peptide-1 Receptor and Glucagon Receptor Dual-Agonist Treatment in a High-Fat Diet-induced Mouse Model

Abstract

Background Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) dual agonist, along with GLP-1R monoagonist, show promise in treating metabolic dysfunction-associated steatotic liver disease (MASLD). Liver fat and iron content are important surrogate markers for disease assessment. However, it remains unclear whether dual agonists provide superior therapeutic benefit over monoagonists for hepatic fat and iron regulation. Purpose To evaluate whether a GLP-1R/GCGR dual agonist offers greater therapeutic efficacy in reducing hepatic fat and iron content compared with a GLP-1R monoagonist in a high-fat diet mouse model using quantitative 9.4-T MRI. Materials and Methods Forty-two male mice were fed a high-fat diet for 13 weeks and then were treated subcutaneously with GLP-1R/GCGR dual agonist (mazdutide), GLP-1R monoagonist (semaglutide), or phosphate-buffered saline (control) every 3 days for 4 weeks. The control group included 14 age-matched male mice that received a standard chow diet and phosphate-buffered saline treatment. MRI scans and tissue samples were obtained at baseline and at 1 and 4 weeks after treatment. MRI-derived proton density fat fraction (PDFF), quantifying hepatic fat content, and R2*, quantifying hepatic iron content, were derived with a 9.4-T MRI scanner. Reductions in PDFF and R2* were compared among the groups using analysis of covariance and Student t tests. Correlations between imaging parameters and histologic analyses were evaluated using Pearson or Spearman correlation coefficients. Results After 4 weeks of treatment, mice treated with the dual agonist showed a greater reduction in PDFF from baseline values compared with mice treated with the monoagonist (median change, -5.59% [IQR, -6.80, -3.84] vs -3.30% [IQR, -3.80, -2.82]; P = .02). At 1 week after treatment, there was no evidence of a difference in PDFF reduction from baseline between the two groups (median change, -2.15% [IQR, -5.10, -1.69] vs -1.24% [IQR, -2.95, -0.78]; P = .19). Decreases in R2* values from baseline were also not significantly different between the groups at 1 week (median change, -53.86 Hz [IQR, -76.79, -43.19] vs -46.17 Hz [IQR, -68.01, -35.04]; P = .50) and 4 weeks (median change, -67.00 Hz [IQR, -79.33, -44.66] vs -57.18 Hz [IQR -78.51, -12.85]; P = .41) after treatment. Liver PDFF was positively correlated with hepatic triglyceride levels (r = 0.82; P < .001) and histologic steatosis scores (r = 0.81; P < .001), as well as R2* values (r = 0.69; P < .001). Conclusion Ultrahigh-field-strength MRI combined with histologic analyses demonstrated that the GLP-1R/GCGR dual agonist more effectively reduced hepatic fat accumulation compared with the GLP-1R monoagonist in a high-fat diet mouse model. MRI-derived liver PDFF and R2* values were correlated with histologic findings. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Yin in this issue.