The Effects of Maternal Fructose Intake on Hepatic Metabolism in Fetal and Neonatal Rat Offspring

Abstract

It is well-established that an adverse early life nutritional environment results in an increased risk of obesity and metabolic syndrome in the offspring. However, very few studies have examined maternal fructose intake as a model, despite its relevance to modern human diets. The current study hypothesised that maternal fructose intake during pregnancy and lactation would alter maternal adaptation to pregnancy and result in changes in fetal and neonatal hepatic metabolism, thereby predisposing offspring to metabolic dysfunction. Methods: Pregnant Wistar rats were time-mated and randomised to either control (CON) or highfructose (FR) diets. Blood and liver samples were collected at embryonic day 21 (E21); postnatal day 2 (P2) and P10. Neonatal stomach contents were analysed as a proxy for milk composition and liver triglyceride and glycogen content was measured. Results: Maternal FR intake resulted in elevated maternal plasma fructose levels, maternal hyperinsulinemia at E21 and increased maternal hepatic glycogen content at P10. At E21, female FR fetuses had increased blood glucose and plasma leptin levels and reduced β-hydroxybutyrate (BHB) levels, compared to CON. Female FR fetuses also demonstrated higher hepatic glycogen content. At P2, female neonates had increased leptin and BHB levels, but lower plasma nonesterified fatty acid (NEFA) levels, accompanied by increased stomach content insulin levels. By P10, female plasma insulin levels were lower and stomach content leptin was elevated compared to CON. Male offspring demonstrated no phenotype at E21, but at P10, FR neonates had elevated plasma fructose, BHB and NEFA levels, decreased blood glucose and plasma insulin levels and increased stomach content leptin levels. At P10, male and female FR neonates also exhibited increased hepatic triglyceride content, compared to CON. Conclusions: The current study demonstrated that maternal fructose intake during pregnancy and lactation resulted in maternal hyperinsulinaemia and increased maternal liver glycogen content, in the absence of changes to body weight or body fat mass. Maternal fructose intake also resulted in age-specific and sex-specific alterations in offspring glucose and lipid metabolism, with female offspring appearing to be more affected in the fetal and early neonatal period and male offspring showing evidence of an altered lipid profile at P10. Further studies are now critical to establish the long term effects of maternal fructose intake on the health and well-being of offspring and determine whether the observed sex differences elicit different risk profiles for metabolic disease into the post-weaning period.