Article

Folic Acid Supplementation during the Juvenile-Pubertal Period in Rats Modifies the Phenotype and Epigenotype Induced by Prenatal Nutrition

Institute of Human Nutrition.
Journal of Nutrition (Impact Factor: 3.88). 05/2009; 139(6):1054-60. DOI: 10.3945/jn.109.104653
Source: PubMed

ABSTRACT

Prenatal nutritional constraint is associated with increased risk of metabolic dysregulation in adulthood contingent on adult diet. In rats, folic acid supplementation of a protein-restricted (PR) diet during pregnancy prevents altered phenotype and epigenotype in the offspring induced by the PR diet. We hypothesized that increasing folic acid intake during the juvenile-pubertal (JP) period would reverse the effects of a maternal PR diet on the offspring. Rats were fed a control (C) or PR diet during pregnancy and AIN93G during lactation. Offspring were weaned on d 28 onto diets containing 1 mg [adequate folate (AF)] or 5 mg [folic acid-supplemented (FS)] folic acid/kg feed. After 28 d, all offspring were fed a high-fat (18% wt:wt) diet and killed on d 84. As expected, offspring of PR dams fed the AF diet had increased fasting plasma triglyceride (TAG) and beta-hydroxybutyrate (betaHB) concentrations. The FS diet induced increased weight gain, a lower plasma betaHB concentration, and increased hepatic and plasma TAG concentration compared with AF offspring irrespective of maternal diet. PPARalpha and glucocorticoid receptor promoter methylation increased in liver and insulin receptor promoter methylation decreased in liver and adipose tissue in FS compared with AF offspring, with reciprocal changes in mRNA expression irrespective of maternal diet. These findings show that increased folic acid intake during the JP period did not simply reverse the phenotype induced by the maternal diet. This may represent a period of plasticity when specific nutrient intakes may alter the phenotype of the offspring through epigenetic changes in specific genes.

Full-text preview

Available from: jn.nutrition.org
  • Source
    • "However, Burdge et al. report increased weight gain and hepatic lipid accumulation in rats fed high-fat diet containing 5 mg/kg folic acid, compared with 1 mg/kg folic acid [48]. Under high fat feeding, excessive folic acid supplementation may promote hepatic lipid accumulation by impairing fatty acid oxidation in the liver through decreased expression of cpt1a [48]. These contradictory findings may be a consequence of differences in the fat content of the diet. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Folate is an essential B vitamin required for the maintenance of AdoMet-dependent methylation. The liver is responsible for many methylation reactions that are used for post-translational modification of proteins, methylation of DNA, and the synthesis of hormones, creatine, carnitine, and phosphatidylcholine. Conditions where methylation capacity is compromised, including folate deficiency, are associated with impaired phosphatidylcholine synthesis resulting in non-alcoholic fatty liver disease and steatohepatitis. In addition, folate intake and folate status have been associated with changes in the expression of genes involved in lipid metabolism, obesity, and metabolic syndrome. In this review, we provide insight on the relationship between folate and lipid metabolism, and an outlook for the future of lipid-related folate research. © 2013 BioFactors, 2013.
    Full-text · Article · May 2014 · BioFactors
    • "Whilst there is strong evidence of altered DNA methylation patterns across the whole genome in response to variation in maternal nutrition during pregnancy, it is not clear how wide the ''window'' for epigenetic programming in response to nutrition may be. Certainly, there is some evidence that a degree of plasticity remains into the pubertal growth phase in rats, as epigenetic marks on the peroxisome proliferator activated receptor alpha promoter respond to the folate content of the diet during this period (Burdge et al. 2009). With a long period of sensitivity to diet, it is of interest to determine whether the state of the epigenome following one set of dietary stimuli, for example in foetal life, can influence the response of the epigenome to a stimulus at a later stage. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Nutrition in early life is a determinant of lifelong physiological and metabolic function. Diseases that are associated with ageing may, therefore, have their antecedents in maternal nutrition during pregnancy and lactation. Rat mothers were fed either a standard laboratory chow diet (C) or a cafeteria diet (O) based upon a varied panel of highly palatable human foods, during lactation. Their offspring were then weaned onto chow or cafeteria diet giving four groups of animals (CC, CO, OC, OO n = 9-10). Livers were harvested 10 weeks post-weaning for assessment of gene and protein expression, and DNA methylation. Cafeteria feeding post-weaning impaired glucose tolerance and was associated with sex-specific altered mRNA expression of peroxisome proliferator activated receptor gamma and components of the insulin signalling pathway (Irs2, Akt1 and IrB). Exposure to the cafeteria diet during the suckling period modified the later response to the dietary challenge. Post-weaning cafeteria feeding only down-regulated IrB when associated with cafeteria feeding during suckling (group OO, interaction of diet in weaning and lactation P = 0.041). Responses to cafeteria diet during both phases of the experiment varied between males and females. Global DNA methylation was altered in the liver following cafeteria feeding in the post-weaning period, in males but not females. Methylation of the IrB promoter was increased in group OC, but not OO (P = 0.036). The findings of this study add to a growing evidence base that suggests tissue function across the lifespan a product of cumulative modifications to the epigenome and transcriptome, which may be both tissue and sex-specific.
    No preview · Article · Jan 2014 · Genes & Nutrition
  • Source
    • "The observation that folic acid supplementation prevented or reversed both the changes in gene expression, (in keeping with observations at later time points of development [55]) and the changes in DNA methylation is of considerable interest. A general disturbance of 1-carbon metabolism associated with maternal protein restriction (suggested by the dysregulation, rescued by folate, of Gnmt in MLP), is one candidate mechanism that may explain this. "
    [Show abstract] [Hide abstract]
    ABSTRACT: A large body of evidence from human and animal studies demonstrates that the maternal diet during pregnancy can programme physiological and metabolic functions in the developing fetus, effectively determining susceptibility to later disease. The mechanistic basis of such programming is unclear but may involve resetting of epigenetic marks and fetal gene expression. The aim of this study was to evaluate genome-wide DNA methylation and gene expression in the livers of newborn rats exposed to maternal protein restriction. On day one postnatally, there were 618 differentially expressed genes and 1183 differentially methylated regions (FDR 5%). The functional analysis of differentially expressed genes indicated a significant effect on DNA repair/cycle/maintenance functions and of lipid, amino acid metabolism and circadian functions. Enrichment for known biological functions was found to be associated with differentially methylated regions. Moreover, these epigenetically altered regions overlapped genetic loci associated with metabolic and cardiovascular diseases. Both expression changes and DNA methylation changes were largely reversed by supplementing the protein restricted diet with folic acid. Although the epigenetic and gene expression signatures appeared to underpin largely different biological processes, the gene expression profile of DNA methyl transferases was altered, providing a potential link between the two molecular signatures. The data showed that maternal protein restriction is associated with widespread differential gene expression and DNA methylation across the genome, and that folic acid is able to reset both molecular signatures.
    Full-text · Article · Dec 2013 · PLoS ONE
Show more