Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been shown to have beneficial effects in T2D, reducing hepatic lipid storage and improving metabolic dysfunction-associated steatotic liver disease. However, sex and reproductive age may influence their effect. We investigated the effect of liraglutide administration (0.2 mg/kg/day subcutaneously for 8 weeks) on metabolic disorders in relation to sex and reproductive age, using male, female and ovariectomized female hereditary hypertriglyceridemic (HHTg) rats as a prediabetic model. Liraglutide improved glucose tolerance in all HHTg rats. Female and ovariectomized (OVX) female rats showed a stronger effect of lipid metabolism and visceral adiposity than males. Moreover, no changes in hepatic triacylglycerol (TAG) accumulation were observed in males. Liraglutide partially reversed ovariectomy effects, such as increased body weight, visceral obesity and impaired glucose tolerance. Compared with males, female and OVX female rats showed more significant changes in hepatic gene expression involved in lipogenesis (Scd-1, Srebp1, Pparγ), fatty acid and lipid metabolism (Pparα, Hmgcr, Srebp2) and fibrosis (Tgfβ), which may improve hepatic lipid metabolism. Females of fertile age showed greater improvements in insulin sensitivity, reductions in ectopic lipid accumulation, and improvements in lipid metabolism. Depending on sex and reproductive status, liraglutide can mitigate fatty liver before diabetes onset.
Conclusions
The results suggest that sex and reproductive age could be vital factors in determining the efficacy of liraglutide with regard to its metabolic effects. In a prediabetic model, liraglutide treatment improved glucose tolerance independently of sex and reproductive age. However, prediabetic females experienced a reduction in hepatic lipid accumulation and exhibited greater improvements in insulin sensitivity and hepatic lipid metabolism compared to prediabetic males. Both fertile and ovariectomized females observed a favorable effect of liraglutide on hepatic lipid accumulation and visceral adiposity; however, the beneficial effect on insulin sensitivity in prediabetic females was reduced after ovariectomy. Our findings suggest that the response to liraglutide treatment may vary according to sex and reproductive age, emphasizing the need for an individualized approach in people with prediabetes.
Published: 9 June 2026
