Proceedings of The Physiological Society

Physiology 2015 (Cardiff, UK) (2015) Proc Physiol Soc 34, C64

Oral Communications

Metformin treatment in obese pregnant mice reduces hepatic steatosis in the adult offspring

M. E. Lewis1, H. N. Thomas1, C. D. Byrne1, F. R. Cagampang1

1. Institute of Developmental Sciences, University of Southampton Faculty of Medicine, Southampton General Hospital (mailpoint 887), Southampton, SO16 6YD, United Kingdom.

Introduction: Prevalence of maternal obesity is rising, contributing to increased risk of metabolic disease, such as non-alcoholic fatty liver disease (NAFLD), in adult offspring. Maternal lifestyle changes have little impact on reducing the offspring's risk, highlighting the need for alternative treatments. Metformin (MET) is used to treat gestational diabetes; it reduces maternal hyperglycaemia and inflammation. However, the impact of MET treatment during obese pregnancy on offspring NAFLD risk is unknown. Aims: To investigate the effects of MET treatment in obese pregnant mice on expression of genes involved in lipid homeostasis and on the degree of hepatic steatosis in adult offspring livers. Methods: Female C57/BL6J mice (n=18) were fed a control (C, 7% kcal fat) or a high-fat diet (HF, 45% kcal fat) 6 weeks prior to mating through, pregnancy and lactation. Half of C and HF dams were given MET in drinking water (250mg/kg bodyweight/day) during pregnancy and lactation. Female offspring were weaned onto C or HF diet, creating 8 groups (n=5-8/group): from untreated dams C/C, C/HF, HF/C & HF/HF and from MET-treated dams Cm/C, Cm/HF, HFm/C & HFm/HF. Offspring were killed at 30 weeks of age. A portion of their left livers was fixed and processed for histological examination. The rest was snap-frozen for gene expression analysis. Blinded point counting and Kleiner scoring was used to assess steatosis, inflammation and hepatocyte ballooning in stained liver sections. Expression of genes involved in hepatic de novo lipogenesis (FAS, ACC, ACLY) and fatty acid b-oxidation (CPT1) was measured by quantitative real-time RT-PCR. Data was analysed using a mixed effects model. Results: Maternal and/or postnatal HF diet increased steatosis in offspring livers. Treating obese pregnant dams with MET reduced steatosis in HFm/C vs HF/C livers (0.32 fold, p<0.05), but not in HFm/HF vs HF/HF or Cm/C vs C/C. HF-fed offspring from MET-treated lean dams (Cm/HF) had increased hepatic steatosis (2.07 fold, p<0.001) vs C/HF. Maternal HF diet increased ACC (1.92 fold, p<0.05) and FAS (1.89 fold, p<0.05) expression in HF/C & HF/HF vs C/C livers. Postnatal HF diet increased hepatic ACC (2.18 fold, p<0.01), ACLY (1.94 fold, p<0.001) and FAS (1.90 fold, p<0.001) in C/HF & HF/HF vs C/C mice. MET exposure did not change expression of these genes. However, hepatic CPT1 was reduced in offspring from MET-treated lean dams (Cm/C & Cm/HF) vs those of untreated dams (2.28 fold, p<0.05). Conclusions: MET treatment in obese pregnant dams offers some protection against offspring developing hepatic steatosis. Thus MET may reduce the burden of maternal obesity on the offspring's future health. However, MET treatment in lean pregnant mothers predisposes offspring to increased hepatic steatosis. Caution should therefore be taken when prescribing MET to these women.

Where applicable, experiments conform with Society ethical requirements