Pre-pregnancy treatment of semaglutide improves high-fat-diet-induced placental and fetal hypothalamic alterations in a sex-specific manner in rats

Abstract Introduction The impact of obesity on pregnancy outcomes and offspring health has received increasing attention. Semaglutide have been shown to have significant effects on weight management. This study aims to evaluate whether Pre-pregnancy Semaglutide Intervention (PpSI) improves maternal metabolic disorders before and during pregnancy, affects placental function and fetal hypothalamic neuropeptide expression during late-gestation and its underlying mechanisms. Methods In this study, female SD rats were divided into three groups: control diet (CHOW), high-fat diet (HFD), and high-fat diet with PpSI. After mating with males, maternal metabolic outcomes, placental morphology, nutrient transport, and fetal hypothalamic gene expression were assessed on gestational Day 20. Results PpSI significantly reduced pre-pregnancy weight gain and gestational weight gain of the dams compared with the HFD group. It also reduced maternal blood lipid levels before and during pregnancy. In male placentas of HFD group, the thickness of the labyrinth was decreased, the mRNA expression of amino acid transporters was upregulated, and the phosphorylation of STAT3 and ERK1/2 was increased, while PpSI normalized these changes. In male fetuses, maternal HFD decreased plasma leptin levels, reduced hypothalamic STAT3 signaling and appetite-related gene expression, while pre-pregnancy semaglutide intervention improved these changes. Compared with males, maternal HFD had less effect on placenta or fetal hypothalamic leptin signaling in females. Conclusion PpSI improves maternal lipid metabolism before and during pregnancy, and improves placental nutritional transport and fetal hypothalamic appetite-related gene expression, which provides a potential strategy for pre-pregnancy intervention in obese women.