Sex-Specific and Reproductive Status-Dependent Effects of Liraglutide on Metabolic Disorders Associated with Prediabetes

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.