Metformin mitigates placental dysfunction by modulating gene expressions in a high-fat diet-induced rat model

Background: Maternal obesity impairs placental development and function, contributing to adverse fetal outcomes through disrupted gene regulation and metabolic homeostasis. Metformin, an insulin-sensitizing agent, may mitigate these effects by modulating placental molecular pathways, but its comprehensive impact under obesity-complicated pregnancy remains unclear. Objective: To investigate whether metformin restores placental gene expression and improves placental and maternal metabolic outcomes in a rat model of maternal obesity induced by a high-fat diet (HFD). Methods: Female Sprague-Dawley rats were fed either a control diet or a HFD for six weeks prior to and throughout pregnancy. During gestation, a subset of HFD-fed rats received metformin (500 mg/kg/day) administered via drinking water. Maternal glucose tolerance was assessed in late pregnancy. On gestational day 21, maternal metabolic parameters, placental and fetal weights were assessed. Placental mRNA expression of genes involved in the renin-angiotensin system (RAS), nutrient-sensing (AMPK/SIRT), and nutrient transport (GLUTs, SNATs, AdipoRs) was quantified using qPCR. Results: HFD-fed dams exhibited increased maternal body weight, total fat mass, GPT levels, glucose intolerance, and placental overgrowth. Metformin significantly reversed these effects and improved glucose tolerance without affecting insulin sensitivity. At the molecular level, HFD downregulated key genes involved in RAS, AMPK/SIRT, and nutrient transport. Metformin treatment restored or upregulated the expression of these genes to near-control levels. Conclusion: Metformin mitigates HFD-induced placental dysfunction by restoring vascular, metabolic, and transport gene networks, improving placental efficiency and maternal metabolic status. These findings support metformin's potential to enhance intrauterine conditions in obesity-complicated pregnancies and align with the DOHaD hypothesis, though long-term offspring outcomes require further investigation.