[6S]-5-Methyltetrahydrofolic Acid and Folic Acid Pregnancy Diets Differentially Program Metabolic Phenotype and Hypothalamic Gene Expression of Wistar Rat Dams Post-Birth

Abstract

[6S]-5-methyltetrahydrofolic acid (MTHF) is a proposed replacement for folic acid (FA) in diets and prenatal supplements. This study compared the effects of these two forms on maternal metabolism and hypothalamic gene expression. Pregnant Wistar rats received an AIN-93G diet with recommended FA (1X, 2 mg/kg, control), 5X-FA or equimolar levels of MTHF. During lactation they received the control diet and then a high fat diet for 19-weeks post-weaning. Body weight, adiposity, food intake, energy expenditure, plasma hormones, folate, and 1-carbon metabolites were measured. RNA-sequencing of the hypothalamus was conducted at parturition. Weight-loss from weaning to 1-week post-weaning was less in dams fed either form of the 5X vs. 1X folate diets, but final weight-gain was higher in 5X-MTHF vs. 5X-FA dams. Both doses of the MTHF diets led to 8% higher food intake and associated with lower plasma leptin at parturition, but higher leptin at 19-weeks and insulin resistance at 1-week post-weaning. RNA-sequencing revealed 279 differentially expressed genes in the hypothalamus in 5X-MTHF vs. 5X-FA dams. These findings indicate that MTHF and FA differ in their programing effects on maternal phenotype, and a potential adverse role of either form when given at the higher doses.

Conversion of calcium‐l‐methylfolate and (6S)‐5‐methyltetrahydrofolic acid glucosamine salt into dietary folate equivalents

“…Parameters investigated were concentrations of RBC folate (Pérez‐Conesa et al., 2009), PTF (Pérez‐Conesa et al., 2009; Tactacan et al., 2010), plasma 5‐MTHF (Pannia et al., 2021), egg folate (Tactacan et al., 2010), liver folate (Pérez‐Conesa et al., 2009; Tactacan et al., 2010) and liver 5‐MTHF (Pérez‐Conesa et al., 2009; Pannia et al., 2021).…”

“…2) (P érez-Conesa et al, 2009) and one in pregnant rats and assessed as having a high RoB (Tier 3)(Pannia et al, 2021). Two studies used an unspecified form of5-MTHF (P érez-Conesa et al, 2009;Tactacan et al, 2010) and one used CaLMF(Pannia et al, 2021). The number of animals per group ranged between 6 (P érez-Conesa et al, 2009) and 16-18(Pannia et al, 2021).Parameters investigated were concentrations of RBC folate(P érez-Conesa et al, 2009), PTF (P érez-Conesa et al, 2009;Tactacan et al, 2010), plasma 5-MTHF(Pannia et al, 2021), egg folate(Tactacan et al, 2010), liver folate(P érez-Conesa et al, 2009;Tactacan et al, 2010) and liver 5-MTHF (P érez-…”

“…2) (P érez-Conesa et al, 2009) and one in pregnant rats and assessed as having a high RoB (Tier 3)(Pannia et al, 2021). Two studies used an unspecified form of5-MTHF (P érez-Conesa et al, 2009;Tactacan et al, 2010) and one used CaLMF(Pannia et al, 2021).…”

Associations of Maternal rs1801131 Genotype in MTHFR and Serum Folate and Vitamin B12 with Gestational Diabetes Mellitus in Chinese Pregnant Women

“…This also explains why the relationship between folate, B 12 , and GDM is more dependent on the genotype of rs1801131 ( Table 4 and Figure 2 ). More recently, an animal study indicated that dams that feed higher levels of 5-methyl-THF during pregnancy gained significantly more weight than dams that provide folic acid [ 40 ]. Their findings suggested that high-dose 5-methyl-THF exposure may play a role in the development of metabolic disease.…”

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

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