Retatrutide Improves Steatohepatitis in an Accelerated Mouse Model of Diet-Induced Steatohepatitis with a Fructose Binge

Fructose consumption contributes to metabolic dysfunction-associated steatohepatitis (MASH). Retatrutide is a novel triple receptor agonist that improves obesity and hepatic steatosis in humans. The aims of this study were to develop a shortened and clinically relevant dietary mouse model of diet-induced steatohepatitis, and to evaluate the effects of a retatrutide intervention in this model. C57BL/6N mice were subjected to a single fructose binge (10 mg/g body weight), or a new 31-day mouse model of diet-induced steatohepatitis using western diet, fructose and sucrose in the drinking water, and a final fructose binge with or without retatrutide. A single fructose binge resulted in significantly elevated alanine aminotransferase (ALT) and hepatic triglyceride levels in female mice after 6 hours; male mice showed less hepatotoxicity. The novel 31-day feeding model significantly increased body weight, ALT levels, hepatic triglycerides and cholesterol, and hepatic inflammatory markers in female and male mice compared with their chow-fed controls. The overall hepatic gene expression profile per RNA sequencing of treated mice correlated with that of human MASH in children and adults. Retatrutide intervention over the final 2 weeks of the 31-day mouse model significantly reduced body weight, ALT levels, hepatic triglycerides and cholesterol, and hepatic inflammatory markers in female mice compared with their vehicle-treated counterparts. Our findings indicate that female mice develop more severe liver injury due to a single fructose binge than males. The novel 31-day mouse model induces robust steatohepatitis and correlates with human disease. An intervention with retatrutide improves steatohepatitis in this shortened mouse model.