Background: Maternal obesity and diabetes are increasingly prevalent in pregnancy and may increase the baby’s risk of metabolic disease in adult life. However, the mechanisms underlying the effect of maternal obesity on the fetus are not well understood, though it is likely to be mediated via the placenta. Metformin1 is an oral anti-diabetic drug which improves glycaemic control and has been safely used to improve the metabolic outcomes in obese pregnant mothers. However, its effects on the placenta are poorly understood.Aim: To investigate the effect of maternal high fat diet and metformin treatment during pregnancy on placental expression of the insulin responsive gene Insig1 and genes involved in glucose and lipid transport in mice.Methods: Female C57BL6 mice (n=22) were exposed to the independent variables ‘diet’ (control diet= 7%kcal fat, or high-fat diet= 45% kcal fat) for 6 weeks before conception and during pregnancy, and ‘treatment’ (control treatment= no metformin, or metformin treatment= metformin in drinking water at 250mg/kg/day) during pregnancy. Pregnant dams were killed by cervical dislocation on day 16 of pregnancy. Placentas were collected, snap frozen and stored at -80oC. There were 4 placental groups: control diet with control treatment (CC) (n=12), control diet with metformin treatment (CM) (n=15), high-fat diet with control treatment (HFC) (n=18), and high-fat diet with metformin treatment (HFM) (n=21). RNA was extracted and converted to cDNA and the expression of the insulin induced gene Insig1, the glucose transporters Glut1 and Glut3, lipoprotein lipase (Lpl) and the fatty acid transporter Fatp assessed using quantitative real-time RT-PCR. Data was expressed relative to two housekeeping genes, Ywhaz and β-Actin. Statistical analysis was performed by two-way analysis of variance (ANOVA). Results: High-fat diet significantly reduced placental expression of Glut1 (p<0.05) and Insig1 expression (p<0.01). There was a trend towards lower expression of Glut3 (p=0.054). Metformin significantly reduced placental expression of Glut3 (p<0.01), Insig1 (p<0.05), Lpl (p<0.01) and Fatp (p<0.05). No significant interactions between high-fat diet and metformin were found.Conclusion: Maternal high fat diet and metformin treatment during pregnancy differentially altered placental gene expression suggesting that their effects are mediated by different pathways. Our results demonstrate that the placenta is responding to signals in the maternal environment and further work is required to determine whether these changes in placental gene expression are a direct effect on the placenta or secondary to effects on the mother. The potential effects of metformin on placental function should also be further investigated.