Excess folic acid supplementation increases adiposity and impacts insulin sensitivity in female mice during pregnancy and has sex-specific effects on fetal offspring

We determined the effects of excess folic acid supplementation (5x recommendation) on maternal and fetal offspring metabolic health. Using a mouse (female C57BL/6J) model of gestational dibetes (GDM; 45% kcal fat diet) and control mice (10% kcal diet) we show that folic acid supplementation increased weight gain and fat mass in both GDM and control mice but improved insulin sensitivity in GDM mice and worsened insulin sensitivity in control mice. We found no unmetabolized folic acid in liver from supplemented mice suggesting the metabolic effects of folic acid supplementation may not be due to unmetabolized folic acid. Male fetal (gestational day 18.5) offspring from folic acid supplemented dams (GDM and control) had greater beta cell mass and density than those from unsupplemented dams; this was not observed in female offspring. Differential sex-specific hepatic gene expression profiles were observed in the offspring from supplemented dams but this differed between GDM and controls. Our findings suggest that folic acid supplementation affects insulin sensitivity in female mice, but is dependent on their metabolic phenotype, and has sex-specific effects on offspring pancreas and liver. Overall design: Female C57BL/6J) mouse model of GDM (45% kcal fat diet) and control mice (10% kcal diet), with and without supplemental folic acid (2 or 10 mg/kg diet folic acid). On diet for 13 weeks before breeding and throughout pregnancy. Liver tissue from male and female fetal offpsring (gestational day 18.5) of each maternal diet group was sequenced (bulk RNA-seq).