Maternal obesity is associated with increased risk of offspring metabolic dysfunction in adulthood. Lipotoxicity, a metabolic syndrome, has been linked with gluconeogenic changes in clinical and animal studies. The impact of maternal obesity on fetal gluconeogenesis at embryonic day (E)14.5, is unknown. We hypothesize that a maternal high-fat diet (HFD) will result in increased fetal liver gluconeogenesis.
Four-week-old C57BL/6 genetically-standardized laboratory mice were fed a control standard purified diet (CON; 17% kcal fat) (n=7) or HFD (60% kcal fat) (n=9) for 6 weeks prior to mating with control fed C57BL/6 males. They were maintained on this diet throughout gestation. Observation of a vaginal plug confirmed pregnancy and designated E0.5. Dams were sacrificed at E14.5, and maternal and fetal livers were collected. Transcript levels of key liver gluconeogenic enzymes were investigated by RT-qPCR.
High-fat females weighed more than controls at the time of mating and throughout gestation. At E14.5, maternal blood glucose and circulating insulin and leptin were elevated in high-fat dams. mRNA of maternal cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), a key enzyme in the gluconeogenic pathway, was significantly reduced (p<0.0001) in livers of high-fat dams. Maternal hepatic nuclear factor 4 alpha (HNF4α) mRNA, a known transcription activator of PEPCK, was decreased (p=0.0004), along with mRNA of the upstream insulin receptor substrate 2 (IRS2) (p=0.0018) in high-fat livers. Fetal PEPCK-C (p=0.0068) and pyruvate carboxylase (p=0.0003) mRNA levels were also decreased in the high-fat livers.
Maternal HFD is associated with downregulated mRNA transcript levels of major gluconeogenic enzymes in the maternal and fetal liver at E14.5. This does not support the hypothesis and is likely due to an overabundance of triglycerides and altered maternal-fetal glucose gradient. The altered gluconeogenic profile in the maternal and fetal liver at E14.5 may underlie the increased risk for offspring metabolic dysfunction later in life. Future research should investigate lipid metabolism and the expression of gluconeogenic factors.