Choline Supplementation Mitigates the Adverse Effects of a High Folic Acid Maternal Diet on Food Intake Regulation in the Offspring

Abstract

Abstract Objectives Folic acid (FA) intake by many women in North America is exceeding recommendations. We have shown that high maternal FA induces methylation-dependent programming of energy regulation associated with an obesogenic phenotype in adult rat offspring. However, it is unclear if this is a direct effect of high FA or due to an imbalance between FA and other methyl-nutrients (i.e., choline) in the 1-carbon cycle. Unlike FA, choline intake by women is below recommendations and is absent from most prenatal supplements, potentially affecting fetal development. The objective of this study was to examine the mechanisms and effects of choline content in high FA maternal diets on in-utero programming of energy regulation and later-life offspring phenotype. Methods Pregnant Wistar rats were fed an AIN-93 G diet with recommended FA and choline (1X, RFRC, control), or 5X-FA diet with choline at 0.5X-(HFLC), 1X-(HFRC), or 2.5X- (HFHC). In pups at birth, brain and liver 1-carbon metabolites, hypothalamic DNA methyltransferase (DNMT) activity and global DNA methylation (5-mC%) were measured. At weaning, one male pup/dam was fed the control diet and weekly weight-gain and food intake were recorded for 20 weeks. Results Offspring born to dams on the HFLC and HFRC, but not HFHC diet, had higher food intake (P < 0.05) and weight-gain (P < 0.01) than controls. In liver at birth, free choline was lower in HFHC than in HFLC pups, but betaine was unaffected. In contrast, in brains, betaine but not free choline concentrations, directly reflected the maternal choline diets. These results suggest that choline may modulate central food intake pathways via the methyl-donor betaine, warranting further investigation. Hypothalamic DNMT activity was highest (P < 0.05) in HFLC pups but global methylation was not affected. Thus, gene expression by RNA sequencing and gene-specific methylation in the hypothalamus is in progress to elucidate the mechanisms underlying the observed phenotype. Conclusions Increased maternal choline mitigates the high FA diet induced increase in body weight and food intake in the adult offspring and results in tissue-specific changes in 1-carbon metabolism at birth. These findings have potential application to human health, providing support to optimize choline and FA intakes by women of childbearing age. Funding Sources CIHR-INMD.