Obesity and Placental Function

Abstract

An increasing number of women of reproductive age are obese which affects the continuum of pregnancy and is associated with an increased incidence of adverse maternal and fetal outcomes, including preeclampsia, preterm birth, stillbirth, congenital anomalies, and macrosomia. Maternal obesity is associated with an increased incidence of metabolic and cardiovascular disease later in life in the mother and in the offspring who are developmentally programed by the obese pregnancy environment. The placenta transduces and mediates the effect of the adverse maternal environment to the fetus. The obese maternal environment is characterized by hyperlipidemia and an exaggerated state of inflammation and oxidative stress compared with normal pregnancy. Heightened inflammation and oxidative/nitrative stress are found in the placenta in association with placental dysfunction. We have described reduced mitochondrial respiration and ATP generation in trophoblast isolated from placentas of obese compared with lean women, again suggesting compromised placental function. In utero development exhibits sexual dimorphism with the male fetus at greater risk of poor outcome. We have shown dimorphism in inflammation-mediated regulation of trophoblast mitochondrial respiration. There is also increasing evidence that the obese in utero environment may cause epigenetic changes in placenta leading to altered function.

Keywords

placenta - obesity - inflammation - mitochondria - oxidative stress - epigenetics

• References

• 1 Yogev Y, Catalano PM. Pregnancy and obesity. Obstet Gynecol Clin North Am 2009; 36 (2) 285-300 , viii
• 2 Trasande L, Lee M, Liu Y, Weitzman M, Savitz D. Incremental charges, costs, and length of stay associated with obesity as a secondary diagnosis among pregnant women. Med Care 2009; 47 (10) 1046-1052
• 3 Reece EA. Obesity, diabetes, and links to congenital defects: a review of the evidence and recommendations for intervention. J Matern Fetal Neonatal Med 2008; 21 (3) 173-180
• 4 Vasudevan C, Renfrew M, McGuire W. Fetal and perinatal consequences of maternal obesity. Arch Dis Child Fetal Neonatal Ed 2011; 96 (5) F378-F382
• 5 Baeten JM, Bukusi EA, Lambe M. Pregnancy complications and outcomes among overweight and obese nulliparous women. Am J Public Health 2001; 91 (3) 436-440
• 6 Sebire NJ, Jolly M, Harris JP , et al. Maternal obesity and pregnancy outcome: a study of 287,213 pregnancies in London. Int J Obes Relat Metab Disord 2001; 25 (8) 1175-1182
• 7 Wou K, Ouellet MP, Chen MF, Brown RN. Comparison of the aetiology of stillbirth over five decades in a single centre: a retrospective study. BMJ Open 2014; 4 (6) e004635
• 8 Yao R, Ananth CV, Park BY, Pereira L, Plante LA ; Perinatal Research Consortium. Obesity and the risk of stillbirth: a population-based cohort study. Am J Obstet Gynecol 2014; 210 (5) 457.e1-457.e9
• 9 Aune D, Saugstad OD, Henriksen T, Tonstad S. Maternal body mass index and the risk of fetal death, stillbirth, and infant death: a systematic review and meta-analysis. JAMA 2014; 311 (15) 1536-1546
• 10 Ehrenberg HM, Durnwald CP, Catalano P, Mercer BM. The influence of obesity and diabetes on the risk of cesarean delivery. Am J Obstet Gynecol 2004; 191 (3) 969-974
• 11 Watkins ML, Botto LD. Maternal prepregnancy weight and congenital heart defects in offspring. Epidemiology 2001; 12 (4) 439-446
• 12 Ehrenberg HM, Mercer BM, Catalano PM. The influence of obesity and diabetes on the prevalence of macrosomia. Am J Obstet Gynecol 2004; 191 (3) 964-968
• 13 Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 2002; 25 (10) 1862-1868
• 14 Myatt L. Placental adaptive responses and fetal programming. J Physiol 2006; 572 (Pt 1) 25-30
• 15 Liguori A, D'Armiento FP, Palagiano A , et al. Effect of gestational hypercholesterolaemia on omental vasoreactivity, placental enzyme activity and transplacental passage of normal and oxidised fatty acids. BJOG 2007; 114 (12) 1547-1556
• 16 Barker DJ. The origins of the developmental origins theory. J Intern Med 2007; 261 (5) 412-417
• 17 Barker DJ, Bagby SP, Hanson MA. Mechanisms of disease: in utero programming in the pathogenesis of hypertension. Nat Clin Pract Nephrol 2006; 2 (12) 700-707
• 18 Chu SY, Kim SY, Lau J , et al. Maternal obesity and risk of stillbirth: a metaanalysis. Am J Obstet Gynecol 2007; 197 (3) 223-228
• 19 Frias AE, Morgan TK, Evans AE , et al. Maternal high-fat diet disturbs uteroplacental hemodynamics and increases the frequency of stillbirth in a nonhuman primate model of excess nutrition. Endocrinology 2011; 152 (6) 2456-2464
• 20 Rogers LK, Velten M. Maternal inflammation, growth retardation, and preterm birth: insights into adult cardiovascular disease. Life Sci 2011; 89 (13–14) 417-421
• 21 Clifton VL. Review: Sex and the human placenta: mediating differential strategies of fetal growth and survival. Placenta 2010; 31 (Suppl): S33-S39
• 22 Eriksson JG, Kajantie E, Osmond C, Thornburg K, Barker DJ. Boys live dangerously in the womb. Am J Hum Biol 2010; 22 (3) 330-335
• 23 Stark MJ, Wright IM, Clifton VL. Sex-specific alterations in placental 11beta-hydroxysteroid dehydrogenase 2 activity and early postnatal clinical course following antenatal betamethasone. Am J Physiol Regul Integr Comp Physiol 2009; 297 (2) R510-R514
• 24 Sood R, Zehnder JL, Druzin ML, Brown PO. Gene expression patterns in human placenta. Proc Natl Acad Sci U S A 2006; 103 (14) 5478-5483
• 25 Scott NM, Hodyl NA, Murphy VE , et al. Placental cytokine expression covaries with maternal asthma severity and fetal sex. J Immunol 2009; 182 (3) 1411-1420
• 26 Osei-Kumah A, Smith R, Jurisica I, Caniggia I, Clifton VL. Sex-specific differences in placental global gene expression in pregnancies complicated by asthma. Placenta 2011; 32 (8) 570-578
• 27 Mao J, Zhang X, Sieli PT, Falduto MT, Torres KE, Rosenfeld CS. Contrasting effects of different maternal diets on sexually dimorphic gene expression in the murine placenta. Proc Natl Acad Sci U S A 2010; 107 (12) 5557-5562
• 28 Yeganegi M, Leung CG, Martins A , et al. Lactobacillus rhamnosus GR-1 stimulates colony-stimulating factor 3 (granulocyte) (CSF3) output in placental trophoblast cells in a fetal sex-dependent manner. Biol Reprod 2011; 84 (1) 18-25
• 29 Steier JA, Ulstein M, Myking OL. Human chorionic gonadotropin and testosterone in normal and preeclamptic pregnancies in relation to fetal sex. Obstet Gynecol 2002; 100 (3) 552-556
• 30 Sathishkumar K, Balakrishnan M, Chinnathambi V, Chauhan M, Hankins GD, Yallampalli C. Fetal sex-related dysregulation in testosterone production and their receptor expression in the human placenta with preeclampsia. J Perinatol 2012; 32 (5) 328-335
• 31 Díaz L, Noyola-Martínez N, Barrera D , et al. Calcitriol inhibits TNF-alpha-induced inflammatory cytokines in human trophoblasts. J Reprod Immunol 2009; 81 (1) 17-24
• 32 Jiang B, Kamat A, Mendelson CR. Hypoxia prevents induction of aromatase expression in human trophoblast cells in culture: potential inhibitory role of the hypoxia-inducible transcription factor Mash-2 (mammalian achaete-scute homologous protein-2). Mol Endocrinol 2000; 14 (10) 1661-1673
• 33 Acromite MT, Mantzoros CS, Leach RE, Hurwitz J, Dorey LG. Androgens in preeclampsia. Am J Obstet Gynecol 1999; 180 (1, Pt 1) 60-63
• 34 Christensen A, Froyshov D, Fylling P. Hormone and enzyme assays in pregnancy. IV. The human chorionic somatomammotrophin, placental cystine-aminopeptidase, progesterone and the urinary oestrogens in pregnancies complicated with essential hypertension, mild or severe pre-eclampsia. Acta Endocrinol (Copenh) 1974; 77 (2) 344-355
• 35 Stewart FM, Freeman DJ, Ramsay JE, Greer IA, Caslake M, Ferrell WR. Longitudinal assessment of maternal endothelial function and markers of inflammation and placental function throughout pregnancy in lean and obese mothers. J Clin Endocrinol Metab 2007; 92 (3) 969-975
• 36 Basu S, Haghiac M, Surace P , et al. Pregravid obesity associates with increased maternal endotoxemia and metabolic inflammation. Obesity (Silver Spring) 2011; 19 (3) 476-482
• 37 Aye IL, Lager S, Ramirez VI , et al. Increasing maternal body mass index is associated with systemic inflammation in the mother and the activation of distinct placental inflammatory pathways. Biol Reprod 2014; 90 (6) 129
• 38 Roberts KA, Riley SC, Reynolds RM , et al. Placental structure and inflammation in pregnancies associated with obesity. Placenta 2011; 32 (3) 247-254
• 39 Pathmaperuma AN, Maña P, Cheung SN , et al. Fatty acids alter glycerolipid metabolism and induce lipid droplet formation, syncytialisation and cytokine production in human trophoblasts with minimal glucose effect or interaction. Placenta 2010; 31 (3) 230-239
• 40 Roberts VH, Smith J, McLea SA, Heizer AB, Richardson JL, Myatt L. Effect of increasing maternal body mass index on oxidative and nitrative stress in the human placenta. Placenta 2009; 30 (2) 169-175
• 41 Aye IL, Waddell BJ, Mark PJ, Keelan JA. Oxysterols exert proinflammatory effects in placental trophoblasts via TLR4-dependent, cholesterol-sensitive activation of NF-κB. Mol Hum Reprod 2012; 18 (7) 341-353
• 42 Challier JC, Basu S, Bintein T , et al. Obesity in pregnancy stimulates macrophage accumulation and inflammation in the placenta. Placenta 2008; 29 (3) 274-281
• 43 Kelley DE, He J, Menshikova EV, Ritov VB. Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes. Diabetes 2002; 51 (10) 2944-2950
• 44 Lager S, Jansson N, Olsson AL, Wennergren M, Jansson T, Powell TL. Effect of IL-6 and TNF-α on fatty acid uptake in cultured human primary trophoblast cells. Placenta 2011; 32 (2) 121-127
• 45 Zhu MJ, Du M, Nathanielsz PW, Ford SP. Maternal obesity up-regulates inflammatory signaling pathways and enhances cytokine expression in the mid-gestation sheep placenta. Placenta 2010; 31 (5) 387-391
• 46 Muralimanoharan S, Guo C, Myatt L, Maloyan A. Sexual dimorphism in miR-210 expression and mitochondrial dysfunction in the placenta with maternal obesity. Int J Obes 2015; 39 (8) 1274-1281
• 47 Ghio A, Bertolotto A, Resi V, Volpe L, Di Cianni G. Triglyceride metabolism in pregnancy. Adv Clin Chem 2011; 55: 133-153
• 48 Catalano PM, Huston L, Amini SB, Kalhan SC. Longitudinal changes in glucose metabolism during pregnancy in obese women with normal glucose tolerance and gestational diabetes mellitus. Am J Obstet Gynecol 1999; 180 (4) 903-916
• 49 Aviram A, Hod M, Yogev Y. Maternal obesity: implications for pregnancy outcome and long-term risks-a link to maternal nutrition. Int J Gynaecol Obstet 2011; 115 (Suppl. 01) S6-S10
• 50 Carter AM. Placental oxygen consumption. Part I: in vivo studies—a review. Placenta 2000; 21 (Suppl A): S31-S37
• 51 Jones CT, Rolph TP. Metabolism during fetal life: a functional assessment of metabolic development. Physiol Rev 1985; 65 (2) 357-430
• 52 Bloxam DL, Bobinski PM. Energy metabolism and glycolysis in the human placenta during ischaemia and in normal labour. Placenta 1984; 5 (5) 381-394
• 53 Shekhawat P, Bennett MJ, Sadovsky Y, Nelson DM, Rakheja D, Strauss AW. Human placenta metabolizes fatty acids: implications for fetal fatty acid oxidation disorders and maternal liver diseases. Am J Physiol Endocrinol Metab 2003; 284 (6) E1098-E1105
• 54 Oey NA, den Boer ME, Ruiter JP , et al. High activity of fatty acid oxidation enzymes in human placenta: implications for fetal-maternal disease. J Inherit Metab Dis 2003; 26 (4) 385-392
• 55 Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000; 106 (2) 171-176
• 56 Bartha JL, Visiedo F, Fernández-Deudero A, Bugatto F, Perdomo G. Decreased mitochondrial fatty acid oxidation in placentas from women with preeclampsia. Placenta 2012; 33 (2) 132-134
• 57 Håversen L, Danielsson KN, Fogelstrand L, Wiklund O. Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. Atherosclerosis 2009; 202 (2) 382-393
• 58 Lambertucci RH, Hirabara SM, Silveira LdosR, Levada-Pires AC, Curi R, Pithon-Curi TC. Palmitate increases superoxide production through mitochondrial electron transport chain and NADPH oxidase activity in skeletal muscle cells. J Cell Physiol 2008; 216 (3) 796-804
• 59 Metzger BE, Persson B, Lowe LP , et al; HAPO Study Cooperative Research Group. Hyperglycemia and adverse pregnancy outcome study: neonatal glycemia. Pediatrics 2010; 126 (6) e1545-e1552
• 60 Whyte K, Kelly H, O'Dwyer V, Gibbs M, O'Higgins A, Turner MJ. Offspring birth weight and maternal fasting lipids in women screened for gestational diabetes mellitus (GDM). Eur J Obstet Gynecol Reprod Biol 2013; 170 (1) 67-70
• 61 Xu Y, Wang Q, Cook TJ, Knipp GT. Effect of placental fatty acid metabolism and regulation by peroxisome proliferator activated receptor on pregnancy and fetal outcomes. J Pharm Sci 2007; 96 (10) 2582-2606
• 62 Storch J, Corsico B. The emerging functions and mechanisms of mammalian fatty acid-binding proteins. Annu Rev Nutr 2008; 28: 73-95
• 63 Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008; 7 (6) 489-503
• 64 Biron-Shental T, Schaiff WT, Ratajczak CK, Bildirici I, Nelson DM, Sadovsky Y. Hypoxia regulates the expression of fatty acid-binding proteins in primary term human trophoblasts. Am J Obstet Gynecol 2007; 197 (5) 516.e1-516.e6
• 65 Scifres CM, Chen B, Nelson DM, Sadovsky Y. Fatty acid binding protein 4 regulates intracellular lipid accumulation in human trophoblasts. J Clin Endocrinol Metab 2011; 96 (7) E1083-E1091
• 66 Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006; 116 (11) 3015-3025
• 67 Llurba E, Gratacós E, Martín-Gallán P, Cabero L, Dominguez C. A comprehensive study of oxidative stress and antioxidant status in preeclampsia and normal pregnancy. Free Radic Biol Med 2004; 37 (4) 557-570
• 68 Watson AL, Skepper JN, Jauniaux E, Burton GJ. Susceptibility of human placental syncytiotrophoblastic mitochondria to oxygen-mediated damage in relation to gestational age. J Clin Endocrinol Metab 1998; 83 (5) 1697-1705
• 69 Graziewicz MA, Day BJ, Copeland WC. The mitochondrial DNA polymerase as a target of oxidative damage. Nucleic Acids Res 2002; 30 (13) 2817-2824
• 70 Seo J, Lee KJ. Post-translational modifications and their biological functions: proteomic analysis and systematic approaches. J Biochem Mol Biol 2004; 37 (1) 35-44
• 71 Kossenjans W, Eis A, Sahay R, Brockman D, Myatt L. Role of peroxynitrite in altered fetal-placental vascular reactivity in diabetes or preeclampsia. Am J Physiol Heart Circ Physiol 2000; 278 (4) H1311-H1319
• 72 Lyall F, Gibson JL, Greer IA, Brockman DE, Eis AL, Myatt L. Increased nitrotyrosine in the diabetic placenta: evidence for oxidative stress. Diabetes Care 1998; 21 (10) 1753-1758
• 73 Zamudio S, Kovalenko O, Vanderlelie J , et al. Chronic hypoxia in vivo reduces placental oxidative stress. Placenta 2007; 28 (8–9) 846-853
• 74 Koeck T, Stuehr DJ, Aulak KS. Mitochondria and regulated tyrosine nitration. Biochem Soc Trans 2005; 33 (Pt 6) 1399-1403
• 75 Mele J, Muralimanoharan S, Maloyan A, Myatt L. Impaired mitochondrial function in human placenta with increased maternal adiposity. Am J Physiol Endocrinol Metab 2014; 307 (5) E419-E425
• 76 Lowell BB, Shulman GI. Mitochondrial dysfunction and type 2 diabetes. Science 2005; 307 (5708) 384-387
• 77 Pieczenik SR, Neustadt J. Mitochondrial dysfunction and molecular pathways of disease. Exp Mol Pathol 2007; 83 (1) 84-92
• 78 Højlund K, Wrzesinski K, Larsen PM , et al. Proteome analysis reveals phosphorylation of ATP synthase beta -subunit in human skeletal muscle and proteins with potential roles in type 2 diabetes. J Biol Chem 2003; 278 (12) 10436-10442
• 79 Ritov VB, Menshikova EV, He J, Ferrell RE, Goodpaster BH, Kelley DE. Deficiency of subsarcolemmal mitochondria in obesity and type 2 diabetes. Diabetes 2005; 54 (1) 8-14
• 80 Zurlo F, Lillioja S, Esposito-Del Puente A , et al. Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ. Am J Physiol 1990; 259 (5, Pt 1) E650-E657
• 81 Goodpaster BH, Theriault R, Watkins SC, Kelley DE. Intramuscular lipid content is increased in obesity and decreased by weight loss. Metabolism 2000; 49 (4) 467-472
• 82 Ruggiero C, Ehrenshaft M, Cleland E, Stadler K. High-fat diet induces an initial adaptation of mitochondrial bioenergetics in the kidney despite evident oxidative stress and mitochondrial ROS production. Am J Physiol Endocrinol Metab 2011; 300 (6) E1047-E1058
• 83 Boudina S, Sena S, O'Neill BT, Tathireddy P, Young ME, Abel ED. Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation 2005; 112 (17) 2686-2695
• 84 Chavin KD, Yang S, Lin HZ , et al. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. J Biol Chem 1999; 274 (9) 5692-5700
• 85 Sparks LM, Xie H, Koza RA , et al. A high-fat diet coordinately downregulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 2005; 54 (7) 1926-1933
• 86 Inui M, Martello G, Piccolo S. MicroRNA control of signal transduction. Nat Rev Mol Cell Biol 2010; 11 (4) 252-263
• 87 Chan YC, Banerjee J, Choi SY, Sen CK. miR-210: the master hypoxamir. Microcirculation 2012; 19 (3) 215-223
• 88 Muralimanoharan S, Maloyan A, Mele J, Guo C, Myatt LG, Myatt L. MIR-210 modulates mitochondrial respiration in placenta with preeclampsia. Placenta 2012; 33 (10) 816-823
• 89 Khera A, Vanderlelie JJ, Perkins AV. Selenium supplementation protects trophoblast cells from mitochondrial oxidative stress. Placenta 2013; 34 (7) 594-598
• 90 Panee J, Stoytcheva ZR, Liu W, Berry MJ. Selenoprotein H is a redox-sensing high mobility group family DNA-binding protein that up-regulates genes involved in glutathione synthesis and phase II detoxification. J Biol Chem 2007; 282 (33) 23759-23765
• 91 Bird A. DNA methylation patterns and epigenetic memory. Genes Dev 2002; 16 (1) 6-21
• 92 Petronis A. Human morbid genetics revisited: relevance of epigenetics. Trends Genet 2001; 17 (3) 142-146
• 93 Alegría-Torres JA, Baccarelli A, Bollati V. Epigenetics and lifestyle. Epigenomics 2011; 3 (3) 267-277
• 94 Jones PA, Takai D. The role of DNA methylation in mammalian epigenetics. Science 2001; 293 (5532) 1068-1070
• 95 Rakyan VK, Preis J, Morgan HD, Whitelaw E. The marks, mechanisms and memory of epigenetic states in mammals. Biochem J 2001; 356 (Pt 1) 1-10
• 96 Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat Rev Genet 2009; 10 (5) 295-304
• 97 Smith CJ, Ryckman KK. Epigenetic and developmental influences on the risk of obesity, diabetes, and metabolic syndrome. Diabetes Metab Syndr Obes 2015; 8: 295-302
• 98 Weinmann AS, Bartley SM, Zhang T, Zhang MQ, Farnham PJ. Use of chromatin immunoprecipitation to clone novel E2F target promoters. Mol Cell Biol 2001; 21 (20) 6820-6832
• 99 Kimura AP, Liebhaber SA, Cooke NE. Epigenetic modifications at the human growth hormone locus predict distinct roles for histone acetylation and methylation in placental gene activation. Mol Endocrinol 2004; 18 (4) 1018-1032
• 100 Turner BM. Cellular memory and the histone code. Cell 2002; 111 (3) 285-291
• 101 Boyer LA, Plath K, Zeitlinger J , et al. Polycomb complexes repress developmental regulators in murine embryonic stem cells. Nature 2006; 441 (7091) 349-353
• 102 Gagnidze K, Weil ZM, Faustino LC, Schaafsma SM, Pfaff DW. Early histone modifications in the ventromedial hypothalamus and preoptic area following oestradiol administration. J Neuroendocrinol 2013; 25 (10) 939-955
• 103 Aagaard-Tillery KM, Grove K, Bishop J , et al. Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome. J Mol Endocrinol 2008; 41 (2) 91-102
• 104 Strakovsky RS, Zhang X, Zhou D, Pan YX. Gestational high fat diet programs hepatic phosphoenolpyruvate carboxykinase gene expression and histone modification in neonatal offspring rats. J Physiol 2011; 589 (Pt 11) 2707-2717
• 105 Nelissen EC, van Montfoort AP, Dumoulin JC, Evers JL. Epigenetics and the placenta. Hum Reprod Update 2011; 17 (3) 397-417
• 106 Feinberg AP, Tycko B. The history of cancer epigenetics. Nat Rev Cancer 2004; 4 (2) 143-153
• 107 Chavan-Gautam P, Sundrani D, Pisal H, Nimbargi V, Mehendale S, Joshi S. Gestation-dependent changes in human placental global DNA methylation levels. Mol Reprod Dev 2011; 78 (3) 150
• 108 Koukoura O, Sifakis S, Spandidos DA. DNA methylation in the human placenta and fetal growth [review]. Mol Med Rep 2012; 5 (4) 883-889
• 109 Branco MR, Ficz G, Reik W. Uncovering the role of 5-hydroxymethylcytosine in the epigenome. Nat Rev Genet 2012; 13 (1) 7-13
• 110 Haycock PC, Ramsay M. Exposure of mouse embryos to ethanol during preimplantation development: effect on DNA methylation in the h19 imprinting control region. Biol Reprod 2009; 81 (4) 618-627
• 111 Pirola L, Balcerczyk A, Tothill RW , et al. Genome-wide analysis distinguishes hyperglycemia regulated epigenetic signatures of primary vascular cells. Genome Res 2011; 21 (10) 1601-1615
• 112 Goll MG, Bestor TH. Eukaryotic cytosine methyltransferases. Annu Rev Biochem 2005; 74: 481-514
• 113 Kamei Y, Suganami T, Ehara T , et al. Increased expression of DNA methyltransferase 3a in obese adipose tissue: studies with transgenic mice. Obesity (Silver Spring) 2010; 18 (2) 314-321
• 114 Gut P, Verdin E. The nexus of chromatin regulation and intermediary metabolism. Nature 2013; 502 (7472) 489-498
• 115 Heijmans BT, Tobi EW, Lumey LH, Slagboom PE. The epigenome: archive of the prenatal environment. Epigenetics 2009; 4 (8) 526-531
• 116 Tobi EW, Lumey LH, Talens RP , et al. DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific. Hum Mol Genet 2009; 18 (21) 4046-4053
• 117 Waterland RA, Lin JR, Smith CA, Jirtle RL. Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet 2006; 15 (5) 705-716
• 118 Keyes MK, Jang H, Mason JB , et al. Older age and dietary folate are determinants of genomic and p16-specific DNA methylation in mouse colon. J Nutr 2007; 137 (7) 1713-1717
• 119 Hoile SP, Irvine NA, Kelsall CJ , et al. Maternal fat intake in rats alters 20:4n-6 and 22:6n-3 status and the epigenetic regulation of Fads2 in offspring liver. J Nutr Biochem 2013; 24 (7) 1213-1220
• 120 Hass BS, Hart RW, Lu MH, Lyn-Cook BD. Effects of caloric restriction in animals on cellular function, oncogene expression, and DNA methylation in vitro. Mutat Res 1993; 295 (4–6) 281-289
• 121 Chen PY, Ganguly A, Rubbi L , et al. Intrauterine calorie restriction affects placental DNA methylation and gene expression. Physiol Genomics 2013; 45 (14) 565-576