Xia Huimin, Min Yuqin, Wang Yuhua, Gao Siyu, Wang Hailing, Yan Fuhua, Liu Ruixin, Wang Jiqiu, Gu Xuejiang, Bo Tingting
Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, 197 Ruijin 2nd Rd, Shanghai 200025, China.
Department of Endocrine and Metabolic Diseases, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Radiology. 2025 Aug;316(2):e243780. doi: 10.1148/radiol.243780.
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 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]; = .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]; = .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]; = .50) and 4 weeks (median change, -67.00 Hz [IQR, -79.33, -44.66] vs -57.18 Hz [IQR -78.51, -12.85]; = .41) after treatment. Liver PDFF was positively correlated with hepatic triglyceride levels ( = 0.82; < .001) and histologic steatosis scores ( = 0.81; < .001), as well as R2* values ( = 0.69; < .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. See also the editorial by Yin in this issue.
背景 胰高血糖素样肽-1受体（GLP-1R）和胰高血糖素受体（GCGR）双重激动剂以及GLP-1R单激动剂在治疗代谢功能障碍相关脂肪性肝病（MASLD）方面显示出前景。肝脏脂肪和铁含量是疾病评估的重要替代标志物。然而，双重激动剂在调节肝脏脂肪和铁方面是否比单激动剂具有更好的治疗效果仍不清楚。目的 使用定量9.4-T磁共振成像（MRI）评估在高脂饮食小鼠模型中，与GLP-1R单激动剂相比，GLP-1R/GCGR双重激动剂在降低肝脏脂肪和铁含量方面是否具有更高的治疗效果。材料与方法 42只雄性小鼠接受13周高脂饮食，然后每3天皮下注射GLP-1R/GCGR双重激动剂（玛扎鲁肽）、GLP-1R单激动剂（司美格鲁肽）或磷酸盐缓冲盐水（对照组），共治疗4周。对照组包括14只年龄匹配的雄性小鼠，给予标准饲料饮食和磷酸盐缓冲盐水治疗。在基线以及治疗后1周和4周时进行MRI扫描并获取组织样本。使用9.4-T MRI扫描仪得出MRI衍生的质子密度脂肪分数（PDFF，用于量化肝脏脂肪含量）和R2*（用于量化肝脏铁含量）。使用协方差分析和学生检验比较各组PDFF和R2的降低情况。使用Pearson或Spearman相关系数评估成像参数与组织学分析之间的相关性。结果 治疗4周后，与接受单激动剂治疗的小鼠相比，接受双重激动剂治疗的小鼠的PDFF较基线值有更大幅度降低（中位数变化，-5.59%[四分位间距，-6.80，-3.84]对-3.30%[四分位间距，-3.80，-2.82]；P = 0.02）。治疗1周后，两组间PDFF较基线值降低情况无差异（中位数变化，-2.15%[四分位间距，-5.10，-1.69]对-1.24%[四分位间距，-2.95，-0.78]；P = 0.19）。治疗1周时，两组间R2值较基线值的降低也无显著差异（中位数变化，-53.86 Hz[四分位间距，-76.79，-43.19]对-46.17 Hz[四分位间距，-68.01，-35.04]；P = 0.50），治疗4周时同样无显著差异（中位数变化，-67.00 Hz[四分位间距，-79.33，-44.66]对-57.18 Hz[四分位间距 -78.51，-12.85]；P = 0.41）。肝脏PDFF与肝脏甘油三酯水平（r = 0.82；P < 0.001）、组织学脂肪变性评分（r = 0.81；P < 0.001）以及R,2值（r = 0.69；P < 0.001）呈正相关。结论 超高场强MRI结合组织学分析表明，在高脂饮食小鼠模型中，GLP-1R/GCGR双重激动剂比GLP-1R单激动剂更有效地减少肝脏脂肪堆积。MRI衍生的肝脏PDFF和R2值与组织学结果相关。根据知识共享署名4.0许可协议发布。另见本期Yin的社论。
