Background & aims: Although maternal obesity is an independent risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), the pathogenesis remains unclear. We aimed to evaluate the effect and mechanisms of multigenerational maternal Western diet (WD) on MASLD progression, and test drug candidates.

Methods: Female mice were fed WD from 8 weeks before breeding initiation with a normal chow (NC)-fed male, throughout pregnancy and lactation. Male offspring were weaned onto NC or WD and assessed at the age of 24 days, 10 weeks, and 16 weeks (n = 5-11 per group). Additionally, offspring from dams with hepatic insulin receptor knockout were evaluated (n = 9-12 per group). Serum fibroblast growth factor 21 (FGF21) and mitochondrial open reading frame of 12S rRNA-c (MOTS-c) were measured in adolescents with MASLD with or without a history of maternal obesity. The therapeutic efficacy of FGF21, semaglutide and an amylin analogue was assessed from 8 to 16 weeks of age (n = 8-12 per group).

Results: Starting from weaning age, maternal WD feeding aggravated body weight gain, insulin resistance, steatosis, and inflammation. Fibrosis was only observed in offspring exposed to maternal WD. Mechanistically, the latter exhibited reduced OXPHOS activity. Isolated maternal hepatic insulin resistance partially recapitulated offspring inflammation and fibrosis. Notably, OXPHOS was also downregulated in a transcriptomic dataset of maternal WD feeding in non-human primates. Serum FGF21 and MOTS-c correlated with MASLD severity and maternal obesity in adolescents. Particularly FGF21 treatment ameliorated steatohepatitis and mitochondrial function.

Conclusions: Maternal WD aggravates MASLD in male offspring starting from weaning age, with mitochondrial dysfunction contributing to disease severity. This was reversed by FGF21 agonism.

Impact and implications: The underlying mechanisms of maternal obesity contributing to metabolic dysfunction-associated steatotic liver disease (MASLD) severity in the offspring are not completely understood. Our study characterises the impact of multigenerational maternal Western diet on offspring MASLD development and identifies mitochondrial dysfunction as a contributor to disease severity. In this setting, pharmacological compounds targeting mitochondrial dysfunction appear to have the greatest therapeutic potential.

Keywords: FGF21; MASH; NAFLD; Oxidative phosphorylation.

© 2025 The Author(s).

背景与目的：尽管母体肥胖是代谢功能障碍相关脂肪肝疾病（MASLD）的独立风险因素，但其发病机制尚不清楚。我们旨在评估多代母体西方饮食（WD）对MASLD进展的影响及机制，并测试药物候选物。

方法：雌性小鼠从8周龄开始喂食WD，在与正常饲料（NC）喂养的雄鼠配种后，整个妊娠和哺乳期继续喂食WD。雄性后代断奶后分别用NC或WD喂养，并在24天、10周和16周龄时进行评估（每组n=5-11）。此外，还对母体肝脏胰岛素受体敲除的小鼠后代进行了评估（每组n=9-12）。通过测量MASLD青少年患者血清中的成纤维细胞生长因子21（FGF21）和线粒体开放阅读框12S rRNA-c（MOTS-c），研究了母体肥胖史的影响。从8周到16周龄时，评估了FGF21、司美格鲁肽和一种胰岛素样多肽的治疗效果（每组n=8-12）。

结果：自断奶年龄开始，母体WD喂养加剧了体重增加、胰岛素抵抗、脂肪变性和炎症。仅在暴露于母体WD的小鼠后代中观察到纤维化。机制上，后者表现出氧化磷酸化（OXPHOS）活性降低的现象。隔离的母体肝脏胰岛素抵抗部分再现了后代炎症和纤维化的情况。值得注意的是，在非人灵长类动物接受母体WD喂养时，基因组数据集也显示出线粒体功能下降。血清FGF21和MOTS-c与青少年MASLD严重程度及母体肥胖史呈相关性。特别是FGF21治疗可改善脂肪性肝炎和线粒体功能。

结论：母体WD自断奶年龄开始加剧雄性后代的MASLD，线粒体功能障碍是疾病严重程度的一个贡献因素。这一影响可以通过激活FGF21逆转。

影响与意义：母体肥胖对后代代谢功能障碍相关脂肪肝疾病（MASLD）严重程度的贡献机制尚未完全了解。我们的研究阐明了多代母体西方饮食对后代MASLD发展的影响，并确定线粒体功能障碍是疾病严重程度的一个因素。在这种情况下，针对线粒体功能障碍的药物化合物似乎具有最大的治疗潜力。

关键词：FGF21；MASH；NAFLD；氧化磷酸化。

© 2025 The Author(s).