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Review
. 2012 Jul 15;17(2):282-301.
doi: 10.1089/ars.2011.4381. Epub 2012 Jan 13.

Nutrition, epigenetics, and metabolic syndrome

Junjun Wang  1 , Zhenlong Wu, Defa Li, Ning Li, Scott V Dindot, M Carey Satterfield, Fuller W Bazer, Guoyao Wu
Affiliations
Review

Nutrition, epigenetics, and metabolic syndrome

Junjun Wang et al. Antioxid Redox Signal. .

Abstract

Significance: Epidemiological and animal studies have demonstrated a close link between maternal nutrition and chronic metabolic disease in children and adults. Compelling experimental results also indicate that adverse effects of intrauterine growth restriction on offspring can be carried forward to subsequent generations through covalent modifications of DNA and core histones.

Recent advances: DNA methylation is catalyzed by S-adenosylmethionine-dependent DNA methyltransferases. Methylation, demethylation, acetylation, and deacetylation of histone proteins are performed by histone methyltransferase, histone demethylase, histone acetyltransferase, and histone deacetyltransferase, respectively. Histone activities are also influenced by phosphorylation, ubiquitination, ADP-ribosylation, sumoylation, and glycosylation. Metabolism of amino acids (glycine, histidine, methionine, and serine) and vitamins (B6, B12, and folate) plays a key role in provision of methyl donors for DNA and protein methylation.

Critical issues: Disruption of epigenetic mechanisms can result in oxidative stress, obesity, insulin resistance, diabetes, and vascular dysfunction in animals and humans. Despite a recognized role for epigenetics in fetal programming of metabolic syndrome, research on therapies is still in its infancy. Possible interventions include: 1) inhibition of DNA methylation, histone deacetylation, and microRNA expression; 2) targeting epigenetically disturbed metabolic pathways; and 3) dietary supplementation with functional amino acids, vitamins, and phytochemicals.

Future directions: Much work is needed with animal models to understand the basic mechanisms responsible for the roles of specific nutrients in fetal and neonatal programming. Such new knowledge is crucial to design effective therapeutic strategies for preventing and treating metabolic abnormalities in offspring born to mothers with a previous experience of malnutrition.

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Figures

FIG. 1.
FIG. 1.
Impacts of maternal and paternal nutrition on fetal programming. Either undernutrition or overnutrition of the mother or father affects expression of the fetal genome, which may have lifelong consequences. Thus, alterations in fetal nutrition may result in developmental adaptations that permanently change the structure, physiology, and metabolism of offspring, thereby predisposing individuals to metabolic, endocrine, and cardiovascular diseases in adult life.
FIG. 2.
FIG. 2.
One-carbon unit metabolism for provision of methyl donors in cells. Folate, histidine, methionine, glycine and serine participate in the transfer of one-carbon units for the synthesis of purines and DNA as well as methylation reactions in animals. The enzymes that catalyzed the indicated reactions are: 1) folate reductase; 2) N5-N10-methylene H4-folate dehydrogenase (a trifunctional enzyme possessing N10-formyl H4-folate synthetase, N5-N10-methylene H4-folate dehydrogenase, and N5-N10-methenyl H4-folate cyclohydrolase activities); 3) N10-formyl H4-folate dehydrogenase; 4) serine hydroxymethyl transferase; 5) N5-N10-methylene H4-folate reductase; 6) methionine synthase; 7) S-adenosylmethionine synthase; 8) S-adenosylmethionine as a major methyl group donor in methyltransferase reactions; 9) formiminotransferase-cyclodeaminase (a bifunctional enzyme possessing glutamate formiminotransferase and formimidoyl H4-folate cyclodeaminase activities); 10) serine hydroxymethyl transferase, N5-N10-methenyl H4-folate cyclohydrolase, and spontaneous reaction at pH 4 to 7.0; 11) N5-N10-methenyl H4-folate synthetase; 12) a sequential series of enzymes: histidase, urocanase, and imidazolone propionate hydrolase; 13) thymidylate synthase; 14) formyltransferase; 15) an oxidant for cells; 16) betaine:homocysteine methyltransferase; 17) choline dehydrogenase; and 18) S-adenosylhomocysteine hydrolase. dTMP, deoxythymidine 5'-monophosphate; dUMP, deoxyuridine 5'-monophosphate; Gly, glycine; H4-folate, tetrahydrofolate; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; Ser, serine; Vit, vitamin.
FIG. 3.
FIG. 3.
Biochemical reactions involving DNA methylation and histone modifications. These reactions are localized in specific compartments of the cell. SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine; Ub, ubiquitin.
FIG. 4.
FIG. 4.
Passage of epigenetic information during DNA replication in germlines. When double-stranded DNA is divided into daughter DNA, a specifc DNA methyltransferase can methylate the cytosine in CpG islands of the daughter DNA at the blastocyst stage of conceptus development. Tissue-specific gene expression results from differences in DNA methylation and promoter activity, leading to differentiated somatic cells.
FIG. 5.
FIG. 5.
Roles of histone modifications in the regulation of gene transcription. Methylation of histones, acetylation, or ubiquitination can either activate or repress gene expression, depending on specific histone proteins and the sites of modifications. In general, phosphorylation of histones promotes transcription, DNA repair, and apoptosis. H, histone; K, lysine residue; R, arginine residue.
FIG. 6.
FIG. 6.
Biogenesis of microRNA and its role in the regulation of gene expression. The biogenesis of mature (functional) miRNA from its miRNA gene involves both the nucleus and cytoplasm in mammalian cells. A single-stranded mature (functional) miRNA with approximately 22 nucleotides (nt) binds the 3’-untranslated region of the target mRNA. This usually results in decreased protein synthesis through induction of mRNA deadenylation, reduction of translation initiation, and inhibition of translation elongation. DGCR8, associated protein DGCR8 of Drosha (also known as Pasha); TRBP (transacting RNA-binding protein); miRNA*, passenger strand miRNA for degradation; RISC, RNA-induced silencing complex (RISC) containing several components, including Argonaute proteins, PW182 protein, and fragile X mental retardation protein.
FIG. 7.
FIG. 7.
Roles of macro- and micro-nutrients in epigenetics and physiological responses. Nutrients, particularly amino acids, regulate cellular redox state, the secretion of hormones (e.g., insulin and insulin-like growth factors), physiological functions, and whole-body homeostasis in humans and animals through three mechanisms: (1) the expression of genes; (2) the production of signaling gases and other metabolites; and (3) MTOR activation. S-Adenosylmethionine is the major methyl group donor in cells and its synthesis is affected by amino acids (e.g., methionine, serine, glycine, and histidine), B vitamins (including folate, vitamin B12, and vitamin B6), choline, and creatine. Methylation of DNA and protein contributes to epigenetics, which results in transcriptional activation or inhibition of select genes. Changes in intracellular protein turnover (protein synthesis and degradation) and protein kinase cascades can alter physiological responses in the fetus and offspring. CO, carbon monoxide; 4EBP1, eIF4E-binding protein-1; GH, growth hormone; H2S, hydrogen sulfide; IGF, insulin-like growth factor; MTOR, mechanistic target of rapamycin; NO, nitric oxide; SAM, S-adenosylmethionine; S6K1, ribosomal protein S6 kinase-1; SPP1, secreted phosphoprotein 1.
FIG. 8.
FIG. 8.
Pharmacological and nutritional interventions of epigenetic defects. Epigenetic defects can occur in response to environmental stress (e.g., malnutrition and heat stress), abnormal endocrine status, and abnormal levels of metabolites in the body. Chemically synthesized drugs (e.g., 5'-azacytidine as an inhibitor of DNA methyltransferase), physiological metabolites (e.g., butyrate as an inhibitor of histone deacetylase), specific nutrients (e.g., amino acids and vitamins), or bioactive phytochemicals may be used to prevent and treat epimutations.
FIG. 9.
FIG. 9.
Role of L-arginine in enhancing fetal growth and development in response to maternal undernutrition or overnutrition. Through the tetrahydrobiopterin (BH4)-dependent synthesis of nitric oxide (NO) and production of polyamines from arginine-derived ornithine as well as activation of the mechanistic target of rapamycin (MTOR) signaling pathway, L-arginine can promote embryogenesis and placental vascular growth. Antioxidants are essential to maintain sufficient levels of BH4 in cells for NO synthase (NOS). Enhancement of uteroplacental blood flow ensures adequate transport of nutrients and oxygen from mother to fetus to support fetal growth and development under the conditions of maternal malnutrition. ODC, ornithine decarboxylase.
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