Non-alcoholic fatty liver disease and steatohepatitis are highly associated with obesity and type 2 diabetes mellitus. Cotadutide, a glucagon-like protein-1 receptor (GLP-1R) and glucagon receptor (GCGR) agonist, was shown to reduce blood glycaemia, body weight and hepatic steatosis in people with type 2 diabetes mellitus. Here, we demonstrate that the effects of cotadutide in reducing body weight and food intake and improving glucose control are predominantly mediated through Glp-1 signalling, whereas its action on the liver to reduce lipid content, drive glycogen flux and improve mitochondrial turnover and function are directly mediated through Gcg signalling. This was confirmed by the identification of phosphorylation sites on key lipogenic and glucose metabolism enzymes in liver of mice treated with cotadutide. Complementary metabolomic and transcriptomic analyses implicated lipogenic, fibrotic and inflammatory pathways, consistent with a unique therapeutic contribution of GCGR agonism by cotadutide in vivo. Notably, cotadutide also alleviated fibrosis to a greater extent than liraglutide or obeticholic acid, despite dose adjustment to achieve similar weight loss in two preclinical mouse models of NASH. Thus, cotadutide, via direct hepatic (GcgR) and extrahepatic (Glp-1R) effects, exerts multifactorial improvement in liver function and is a promising therapeutic option for the treatment of steatohepatitis.

非酒精性脂肪肝和脂肪性肝炎与肥胖症和2型糖尿病高度相关。Cotadutide是一种胰高血糖素样蛋白1受体（GLP-1R）和胰高血糖素受体（GCGR）激动剂，被证明可以降低2型糖尿病患者的血糖，体重和肝脂肪变性。在这里，我们证明可卡地肽在减轻体重和食物摄入以及改善葡萄糖控制中的作用主要是通过Glp-1信号传导介导的，而其对肝脏的作用是减少脂质含量，驱动糖原通量并改善线粒体更新和功能。通过Gcg信号直接介导。这通过确认用卡他度肽治疗的小鼠肝脏中主要的脂肪形成和葡萄糖代谢酶的磷酸化位点的确定而得到证实。互补的代谢组学和转录组学分析涉及脂肪生成，纤维化和炎症途径，与可卡肽在体内对GCGR激动剂的独特治疗作用相一致。值得注意的是，尽管在两个NASH临床前小鼠模型中进行了剂量调整以实现相似的体重减轻，但cotadutide仍比利拉鲁肽或奥贝胆酸减轻了更大程度的纤维化。因此，cotadutide通过直接肝（GcgR）和肝外（Glp-1R）的作用，在肝功能方面发挥了多方面的改善作用，是治疗脂肪性肝炎的有前途的治疗选择。尽管在两个NASH临床前小鼠模型中进行了剂量调整以实现相似的体重减轻，但cotadutide仍比利拉鲁肽或奥贝胆酸减轻了更大程度的纤维化。因此，cotadutide通过直接肝（GcgR）和肝外（Glp-1R）的作用，在肝功能方面发挥了多方面的改善作用，是治疗脂肪性肝炎的有希望的治疗选择。尽管在两个NASH临床前小鼠模型中进行了剂量调整以实现相似的体重减轻，但cotadutide仍比利拉鲁肽或奥贝胆酸减轻了更大程度的纤维化。因此，cotadutide通过直接肝（GcgR）和肝外（Glp-1R）的作用，在肝功能方面发挥了多方面的改善作用，是治疗脂肪性肝炎的有前途的治疗选择。