Introduction: The prevalence of obesity and diabetes during pregnancy may increase the risk of obesity and fatty liver disease in adult offspring. Thus there is impetus in improving the metabolic health of pregnant mothers to reduce maternal influence on adult offspring disease risk. This includes pharmacological intervention using the antidiabetic drug metformin in pregnancies complicated with gestational diabetes. However, its impact on fetal hepatic development is unknown.Aims: To investigate the effect of metformin treatment in obese pregnant mice fed a high fat diet on fetal hepatic development and expression of key nutrient sensitive genes.Methods: Female C57/BL6J mice were fed a control diet (C, 7% kcal fat) or high-fat diet (HF, 45% kcal fat) 6 weeks prior to mating through pregnancy. A subset of pregnant C and HF dams were given metformin in drinking water (250mg/kg bodyweight/day) throughout pregnancy, generating four dam groups: C diet without treatment (C, n=4), C diet with metformin (Cm, n=5), HF diet without treatment (HF, n=5) and HF diet with metformin (HFm, n=7). Dams were killed on day 16 of pregnancy by cervical dislocation. Fetal livers were taken and stored at -80°. RNA was extracted from fetal livers and converted to cDNA. Expression of Sirt1, a metabolic sensor central to glucose metabolism, and PGC-1α, a gluconeogenic transcriptional coactivator regulated by Sirt1, was assessed using quantitative real-time RT-PCR. Data presented as means±SEM or fold difference. Mean differences between groups were assessed by two-way ANOVA. Results: Maternal HF diet (p<0.001) and metformin treatment (p<0.01) significantly reduced fetal bodyweight. There was a significant interaction effect between maternal diet and metformin treatment (p<0.01). Metformin significantly reduced body weights of fetuses from Cm dams compared to those from C dams (0.49±0.02g vs 0.64±0.01g, p<0.001); no effect was found in HFm fetuses vs HF fetuses. HF diet significantly reduced fetal liver weight (p<0.001). Metformin reduced fetal liver weight in Cm dams vs C dams (0.029±0.001g vs 0.043±0.001g, p<0.001) but had no impact on HFm fetuses. HF diet exposure reduced fetal liver Sirt1 mRNA levels (p<0.05), whilst increasing PGC-1α levels (p<0.01). Metformin significantly increased Sirt1 expression by 1.5 fold (p<0.001) and reduced PGC-1α expression by 1.5 fold (p<0.01) in HFm vs HF fetuses. Conclusion: Alterations in PGC-1α and Sirt1 gene expression in livers of fetuses from obese dams fed a high fat diet suggest that overnutrition in-utero may prime alterations in fetal metabolism, increasing future metabolic disease risk in the offspring. Changes in Sirt1 and PGC-1α gene expression following metformin treatment during pregnancy suggest that it could provide protection against prolonged metabolic insults.