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 wt), or a new 31-day mouse model of diet-induced steatohepatitis using a 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 h; 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.Female mice are more prone to liver injury due to a single fructose binge compared with male mice. The new 31-day mouse model induces robust steatohepatitis in mice and correlates with MASLD in children and adults. An intervention with retatrutide improves steatohepatitis in this novel mouse model, indicating despite its short duration, the model can be used to trial pharmacological interventions. NEW & NOTEWORTHY
