High Intakes of [6S]-5-Methyltetrahydrofolic Acid Compared with Folic Acid during Pregnancy Programs Central and Peripheral Mechanisms Favouring Increased Food Intake and Body Weight of Mature Female Offspring

Abstract

Supplementation with [6S]-5-methyltetrahydrofolic acid (MTHF) is recommended as an alternative to folic acid (FA) in prenatal supplements. This study compared equimolar gestational FA and MTHF diets on energy regulation of female offspring. Wistar rats were fed an AIN-93G diet with recommended (2 mg/kg diet) or 5-fold (5X) intakes of MTHF or FA. At weaning, female offspring were fed a 45% fat diet until 19 weeks. The 5X-MTHF offspring had higher body weight (>15%), food intake (8%), light-cycle energy expenditure, and lower activity compared to 5X-FA offspring (p < 0.05). Both the 5X offspring had higher plasma levels of the anorectic hormone leptin at birth (60%) and at 19 weeks (40%), and lower liver weight and total liver lipids compared to the 1X offspring (p < 0.05). Hypothalamic mRNA expression of leptin receptor (ObRb) was lower, and of suppressor of cytokine signaling-3 (Socs3) was higher in the 5X-MTHF offspring (p < 0.05), suggesting central leptin dysregulation. In contrast, the 5X-FA offspring had higher expression of genes encoding for dopamine and GABA- neurotransmitter receptors (p < 0.01), consistent with their phenotype and reduced food intake. When fed folate diets at the requirement level, no differences were found due to form in the offspring. We conclude that MTHF compared to FA consumed at high levels in the gestational diets program central and peripheral mechanisms to favour increased weight gain in the offspring. These pre-clinical findings caution against high gestational intakes of folates of either form and encourage clinical trials examining their long-term health effects when consumed during pregnancy.

Serum folate mediates the associations of MTHFR rs1801133 polymorphism with blood glucose levels and gestational diabetes mellitus in Chinese Han pregnant women

“…The above evidence indicates that folate/vitaminB 12 imbalance coupled with pregnant women’s MTHFR rs1801133 CC and rs1801131 TT genotype is more likely to accumulate 5-methyl-THF in the body. Although the role of 5-methyl-THF in the pathogenesis of GDM is unclear, recent animal studies suggested that consuming 5-methyl-THF diets will increase the weight of the dams and their female offspring (35,36) . Therefore, 5-methyl-THF may play a role in GDM occurrence, and further studies are needed to clarify the underlying mechanism.…”

“…Accepted manuscript 5-methyl-THF diets will increase the weight of the dams and their female offspring (35,36) .…”

Folate and Choline: Does It Take Two to Tango in Early Programming of Disease?

“…While studies to date suggest that folate and choline may interact to influence the metabolic phenotypes, different forms of folate (folic acid or methyl folate) and choline (free choline, fat-soluble choline, or oxidized choline) should be considered when examining their programming effects. Comparisons across folate and choline forms are lacking, but different effects can be suggested from the observation that gestational intake of [6S]-5-methyltetrahydrofolic acid compared to folic acid at ×5 requirements favored increased food intake and body weight of mature female offspring [61].…”

Micronutrients in High‐Fat Diet Modify Insulin Resistance and Its Regulatory Genes in Adult Male Mice

“…[4,13] Nutrient modifications of gene methylation patterns in utero were also shown to occur after pregnant rodents are fed highfat, [14,15] protein-deficient diets, [16] or high and low methyl group vitamins. [14,15,17,18] Moreover, high-fat diets (HFD) fed to young mice lead to obesity and insulin resistance (IR) in the adulthood and associated with concurrent changes in gene methylation. [19] However, the effect of supplemental intakes of micronutrients on these changes when added to the diets of adult mice has not been described.…”