Briand François, Dubroca Caroline, Wettstein Guillaume, Grasset Estelle, Breyner Natalia, Bigot Claire, Assaly Rana, Broqua Pierre, Sulpice Thierry
Physiogenex, 280 Rue de l'Hers, Escalquens, 31750, France.
Cardiomedex, 280 Rue de l'Hers, Escalquens, 31750, France.
Eur J Pharmacol. 2025 Sep 15;1003:177945. doi: 10.1016/j.ejphar.2025.177945. Epub 2025 Jul 11.
Obesity is associated with several comorbidities including Heart Failure with preserved Ejection Fraction (HFpEF), Metabolic dysfunction-Associated SteatoHepatitis (MASH), also termed MetALD when MASH patients have increased alcohol intake. The worldwide epidemic of obesity creates a constant need for new therapies and animal models to test their effectiveness. In the present study, we evaluated the effects of the GLP-1 receptor agonist semaglutide and the pan-PPAR agonist lanifibranor in the free choice diet induced obese MASH hamster, a preclinical model with human-like lipoprotein metabolism, MASH and HFpEF. The same model was exposed to ethanol to evaluate the effects of both semaglutide and lanifibranor on chronic alcohol intake. To set up a model of MetALD, obese MASH hamsters were also challenged to alcohol binge drinking and the preventative effects of lanifibranor were evaluated. Compared with vehicle, semaglutide transiently reduced food intake and significantly reduced fructose and alcohol consumption. This effect was associated with significant body weight loss, lower HOMA-IR index of insulin resistance, improved dyslipidemia and HFpEF, but semaglutide only reduced hepatic fat content. Lanifibranor showed the same cardiometabolic benefits but had superior effects in the liver, with significant improvement in MASH and MetALD. As observed in humans, lanifibranor and semaglutide showed multiple metabolic benefits in free-choice diet induced obese hamster models of MASH and MetALD. These hamster models demonstrated good translability regarding the effects observed in clinical trials and will be helpful to evaluate novel therapies targeting obesity and associated comorbidities, including MetALD.
肥胖与多种合并症相关，包括射血分数保留的心力衰竭（HFpEF）、代谢功能障碍相关脂肪性肝炎（MASH），当MASH患者酒精摄入量增加时也称为代谢性酒精性肝病（MetALD）。全球肥胖流行持续需要新的治疗方法和动物模型来测试其有效性。在本研究中，我们评估了胰高血糖素样肽-1受体激动剂司美格鲁肽和泛过氧化物酶体增殖物激活受体激动剂拉尼非诺在自由选择饮食诱导的肥胖MASH仓鼠中的作用，该仓鼠是一种具有类似人类脂蛋白代谢、MASH和HFpEF的临床前模型。将同一模型暴露于乙醇中，以评估司美格鲁肽和拉尼非诺对慢性酒精摄入的影响。为建立MetALD模型，还对肥胖MASH仓鼠进行酒精暴饮挑战，并评估拉尼非诺的预防作用。与赋形剂相比，司美格鲁肽可短暂减少食物摄入量，并显著降低果糖和酒精消耗量。这种作用与体重显著减轻、胰岛素抵抗的HOMA-IR指数降低、血脂异常和HFpEF改善有关，但司美格鲁肽仅降低肝脏脂肪含量。拉尼非诺显示出相同的心脏代谢益处，但在肝脏方面具有更优效果，MASH和MetALD有显著改善。正如在人类中观察到的那样，拉尼非诺和司美格鲁肽在自由选择饮食诱导的肥胖MASH和MetALD仓鼠模型中显示出多种代谢益处。这些仓鼠模型在临床试验中观察到的效果方面具有良好的可转化性，将有助于评估针对肥胖及相关合并症（包括MetALD）的新型疗法。
