Folic Acid Supplementation during the Juvenile-Pubertal Period in Rats Modifies the Phenotype and Epigenotype Induced by Prenatal Nutrition
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.
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- "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 . 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 . These contradictory findings may be a consequence of differences in the fat content of the diet. "
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.BioFactors 05/2014; 40(3). DOI:10.1002/biof.1154 · 3.00 Impact Factor
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- "We investigated the methylation patterns in DMRs of paternally imprinted gene H19, maternally imprinted genes Peg3 (paternally expressed 3), Snrpn (small nuclear ribo nucleo protein N), Igf2r (insulinlike growth factor 2 receptor), and Peg1 in oocytes of control and obese animals and their offspring. Because other studies have shown that the expression of leptin (Lep) and Ppar-α (peroxisome proliferatoractivated receptor α) is regulated by DNA methylation in their promoters and that the two genes are correlated to metabolism (Burdge et al. 2009; Cordero et al. 2011a, 2011b), we also investigated DNA methylation of these two genes. We also investigated DNA methyla tion patterns of intracisternal A particle (IAP) in oocytes. "
ABSTRACT: Maternal obesity has adverse effects on oocyte quality, embryo development and it also affects the health of the offspring. To understand the underlying mechanisms responsible for these negative effects, we investigated the DNA methylation status of several imprinted genes and metabolism-related genes. A high-fat-diet (HFD)-induced mouse model was utilized to analyze the DNA methylation of several imprinted genes and of metabolism-related genes in oocytes from obese mice and in oocytes and liver from their offspring by employing combined bisulfite restriction analysis (COBRA) and bisulfite sequencing (BS). The DNA methylation of imprinted genes in oocytes was not altered in both obese mothers and their offspring, while DNA methylation of metabolism-related genes was changed. The DNA methylation level in the promoter of Leptin was significantly increased and that in the promoter of Ppar-alpha (Ppar-α) was reduced in oocytes of obese mice. The increased methylation of Leptin and decreased methylation of Ppar-α was also observed in the liver of female offspring from obese mothers (OHFD). The mRNA expressions of Leptin and Ppar-α were significantly altered in the liver of offspring from obese mothers. In OHFD oocytes, the DNA methylation level in the promoter of Ppar-α was increased. These results indicate that DNA methylation patterns of several metabolism-related genes are not only changed in oocytes of obese mice, but also in oocytes and liver of their offspring. These data may contribute to elucidating the adverse effects of maternal obesity on reproduction and the offspring's health.Environmental Health Perspectives 12/2013; 122(2). DOI:10.1289/ehp.1307047 · 7.03 Impact Factor
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- "Vitamin B 12 is known to play an important role in regulating the balance of the network of cytokines and growth factors in the central nervous system of the rat . Studies have shown that intervention with folic acid and leptin during particular windows in postnatal life can improve the adverse effects on metabolic syndrome variables in the offspring induced due to maternal protein restriction and undernutrition  . Similarly methyl supplementation has also been shown to reverse epigenetic changes in the glucocorticoid receptors in the rat brain offspring . "
ABSTRACT: Our earlier studies show that maternal diets imbalanced in micronutrients like folic acid and vitamin B12 reduced brain docosahexaenoic acid (DHA) and brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the offspring at birth and postnatal d21. This study followed the offspring till 3months to examine the hypothesis that impaired brain neurotrophins at birth and d21 due to altered maternal micronutrients can be reversed by prenatal omega 3 fatty acid but not a postnatal control diet leading to altered cognition in adult life. Pregnant rats were divided into control and five treatment groups at two levels of folic acid (normal and excess folate) in the presence and absence of vitamin B12 (NFBD, EFB and EFBD). Omega 3 fatty acid supplementation was given to the vitamin B12 deficient groups (NFBDO and EFBDO). Following delivery, 8 dams from each group were shifted to control and remaining continued on same diet. Imbalance in maternal micronutrients up to 3months decreased DHA, BDNF and NGF in cortex and only BDNF in the hippocampus and impaired cognitive performance. Postnatal control diet normalized BDNF in the cortex but not the hippocampus and also altered cognitive performance. Prenatal omega 3 fatty acid supplementation normalized DHA, BDNF and NGF while long term supplementation was not beneficial only when micronutrients were imbalanced. Patterns established at birth are not totally reversible by postnatal diets and give clues for planning intervention studies for improving brain functioning and cognitive abilities.Metabolism: clinical and experimental 07/2013; 62(11). DOI:10.1016/j.metabol.2013.06.002 · 3.61 Impact Factor