Choline and Folic Acid in Diets Consumed during Pregnancy Interact to Program Food Intake and Metabolic Regulation of Male Wistar Rat Offspring

Abstract

North American women consume high folic acid (FA), but most are not meeting the adequate intakes for choline. High-FA gestational diets induce an obesogenic phenotype in rat offspring. It is unclear if imbalances between FA and other methyl-nutrients (i.e., choline) account for these effects. This study investigated the interaction of choline and FA in gestational diets on food intake, body weight, one-carbon metabolism, and hypothalamic gene expression in male Wistar rat offspring. Pregnant Wistar rats were fed an AIN-93G diet with recommended choline and FA [RCRF; 1-fold, control] or high (5-fold) FA with choline at 0.5-fold [low choline and high folic acid (LCHF)], 1-fold [recommended choline and high folic acid (RCHF)], or 2.5-fold [high choline and high folic acid (HCHF)]. Male offspring were weaned to an RCRF diet for 20 wk. Food intake, weight gain, plasma energy-regulatory hormones, brain and plasma one-carbon metabolites, and RNA sequencing (RNA-seq) in pup hypothalamuses were assessed. Adult offspring from LCHF and RCHF, but not HCHF, gestational diets had 10% higher food intake and weight gain than controls (P<0.01). HCHF newborn pups had lower plasma insulin and leptin compared with LCHF and RCHF pups (P<0.05), respectively. Pup brain choline (P<0.05) and betaine (P<0.01) were 22-33% higher in HCHF pups compared with LCHF pups; methionine was ∼23% lower after all high FA diets compared with RCRF (P<0.01). LCHF adult offspring had lower brain choline (P<0.05) than all groups and lower plasma 5-methyltetrahydrofolate (P<0.05) than RCRF and RCHF groups. HCHF adult offspring had lower plasma cystathionine (P<0.05) than LCHF adult offspring and lower homocysteine (P<0.01) than RCHF and RCRF adult offspring. RNA-seq identified 144 differentially expressed genes in the hypothalamus of HCHF newborns compared with controls. Increased choline in gestational diets modified the programming effects of high FA on long-term food intake regulation, plasma energy-regulatory hormones, one-carbon metabolism, and hypothalamic gene expression in male Wistar rat offspring, emphasizing a need for more attention to the choline and FA balance in maternal diets.