Skip to main content
    • Aa
    • Aa

Supplementation with methyl donors during lactation to high-fat-sucrose-fed dams protects offspring against liver fat accumulation when consuming an obesogenic diet

  • P. Cordero (a1), F. I. Milagro (a1) (a2), J. Campion (a1) (a2) and J. A. Martinez (a1) (a2)

Methyl donor supplementation has been reported to prevent obesity-induced liver fat accumulation in adult rats. We hypothesized that this protection could be mediated by perinatal nutrition. For this purpose, we assessed the response to an obesogenic diet (high-fat-sucrose, HFS) during adulthood depending on maternal diet during lactation. Female Wistar rats fed control diet during pregnancy were assigned to four postpartum dietary groups: control, control supplemented with methyl donors (choline, betaine, folic acid, vitamin B12), HFS and HFS supplemented with methyl donors. At weaning, the male offspring was transferred to a chow diet and at week 12th assigned to a control or a HFS diet during 8 weeks. The offspring whose mothers were fed HFS during lactation showed increased adiposity (19%, P<0.001). When fed the HFS diet as adults, offspring whose mothers were HFS supplemented had more body fat (23%, P<0.001) than those from HFS non-supplemented. However, they showed lower liver fat accumulation (−18%, P<0.001). Srebf1, Dnmt1 and Lepr liver mRNA levels increased after adulthood HFS feeding. In those animals HFS fed during adulthood, previous maternal HFS decreased Lepr and Dnmt1 expression levels when compared with c-HFS offspring, while the supplementation of control and HFS-fed dams, respectively, induced higher hepatic Mme and Lepr mRNA levels after adult HFS intake compared with hfs-HFS offspring. In conclusion, maternal HFS diet during lactation influenced the response to an obesogenic diet in the adult progeny. Interestingly, dietary methyl donor supplementation in lactating mothers fed an obesogenic diet reduced liver fat accumulation, but increased adipose tissue storage in adult HFS-fed offspring.

Corresponding author
*Address for correspondence: Prof. J. Alfredo Martinez, Department of Nutrition, Food Science and Physiology, University of Navarra, Irunlarrea Street 1, 31008 Pamplona, Spain.
Linked references
Hide All

This list contains references from the content that can be linked to their source. For a full set of references and notes please see the PDF or HTML where available.

1. DP Guh , W Zhang , N Bansback , Z Amarsi , CL Birmingham , AH Anis . The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis. BMC Public Health. 2009; 9, 88.

2. I Abete , S Navas-Carretero , A Marti , JA Martinez . Nutrigenetics and nutrigenomics of caloric restriction. Prog Mol Biol Transl Sci. 2012; 108, 323346.

4. M Zou , EJ Arentson , D Teegarden , SL Koser , L Onyskow , SS Donkin . Fructose consumption during pregnancy and lactation induces fatty liver and glucose intolerance in rats. Nutr Res. 2012; 32, 588598.

6. T Roseboom , S de Rooij , R Painter . The Dutch famine and its long-term consequences for adult health. Early Hum Dev. 2006; 82, 485491.

7. A Ohlsson , PS Shah . Effects of the September 11, 2001 disaster on pregnancy outcomes: a systematic review. Acta Obstet Gynecol Scand. 2011; 90, 618.

9. Z Vucetic , J Kimmel , K Totoki , E Hollenbeck , TM Reyes . Maternal high-fat diet alters methylation and gene expression of dopamine and opioid-related genes. Endocrinology. 2010; 151, 47564764.

10. RA Waterland , M Travisano , KG Tahiliani , MT Rached , S Mirza . Methyl donor supplementation prevents transgenerational amplification of obesity. Int J Obes (Lond). 2008; 32, 13731379.

12. IM Szeto , PJ Das , A Aziz , GH Anderson . Multivitamin supplementation of Wistar rats during pregnancy accelerates the development of obesity in offspring fed an obesogenic diet. Int J Obes (Lond). 2009; 33, 364372.

13. P Cordero , J Campion , FI Milagro , JA Martinez . Dietary supplementation with methyl donor groups could prevent nonalcoholic fatty liver. Hepatology. 2011; 53, 21512152.

14. P Cordero , AM Gomez-Uriz , J Campion , FI Milagro , JA Martinez . Dietary supplementation with methyl donors reduces fatty liver and modifies the fatty acid synthase DNA methylation profile in rats fed an obesogenic diet. Genes Nutr. 2013; 8, 105113.

15. Y Ding , J He , X Liu , X Chen , C Long , Y Wang . Expression of DNA methyltransferases in the mouse uterus during early pregnancy and susceptibility to dietary folate deficiency. Reproduction. 2012; 144, 91100.

16. P Cordero , J Campion , FI Milagro , JA Martinez . Transcriptomic and epigenetic changes in early liver steatosis associated to obesity: effect of dietary methyl donor supplementation. Mol Genet Metab. 2013; 110, 388395.

17. P Cordero , AM Gomez-Uriz , FI Milagro , J Campion , JA Martinez . Maternal weight gain induced by an obesogenic diet affects adipose accumulation, liver weight, and insulin homeostasis in the rat offspring depending on the sex. J Endocrinol Invest. 2012; 35, 981986.

19. JP Nixon , M Zhang , C Wang , et al.Evaluation of a quantitative magnetic resonance imaging system for whole body composition analysis in rodents. Obesity (Silver Spring). 2010; 18, 16521659.

22. KJ Livak , TD Schmittgen . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001; 25, 402408.

23. L Paternain , AL de la Garza , MA Batlle , FI Milagro , JA Martinez , J Campion . Prenatal stress increases the obesogenic effects of a high-fat-sucrose diet in adult rats in a sex-specific manner. Stress. 2013; 16, 220232.

24. VP Kovacheva , TJ Mellott , JM Davison , et al.Gestational choline deficiency causes global and Igf2 gene DNA hypermethylation by up-regulation of Dnmt1 expression. J Biol Chem. 2007; 282, 3177731788.

25. L Hebbard , J George . Animal models of nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol. 2011; 8, 3544.

26. A Starlard-Davenport , V Tryndyak , O Kosyk , et al.Dietary methyl deficiency, microRNA expression and susceptibility to liver carcinogenesis. J Nutrigenet Nutrigenomics. 2010; 3, 259266.

27. IY Khan , V Dekou , G Douglas , et al. A high-fat diet during rat pregnancy or suckling induces cardiovascular dysfunction in adult offspring. Am J Physiol Regul Integr Comp Physiol. 2005; 288, 127133.

28. ER Flynn , BT Alexander , J Lee , ZM Hutchens Jr., C Maric-Bilkan . High-fat/fructose feeding during prenatal and postnatal development in female rats increases susceptibility to renal and metabolic injury later in life. Am J Physiol Regul Integr Comp Physiol. 2013; 304, 278285.

29. A Alzamendi , D Castrogiovanni , RC Gaillard , E Spinedi , A Giovambattista . Increased male offspring’s risk of metabolic-neuroendocrine dysfunction and overweight after fructose-rich diet intake by the lactating mother. Endocrinology. 2010; 151, 42144223.

30. M Palou , T Priego , J Sanchez , JM Torrens , A Palou , C Pico . Moderate caloric restriction in lactating rats protects offspring against obesity and insulin resistance in later life. Endocrinology. 2010; 151, 10301041.

32. G Perseghin . Lipids in the wrong place: visceral fat and nonalcoholic steatohepatitis. Diabetes Care. 2011; 34, S367S370.

33. E Fabbrini , F Magkos , BS Mohammed , et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A. 2009; 106, 1543015435.

34. S Pooya , S Blaise , M Moreno Garcia , et al. Methyl donor deficiency impairs fatty acid oxidation through PGC-1α hypomethylation and decreased ER-α, ERR-α, and HNF-4α in the rat liver. J Hepatol. 2012; 57, 344351.

35. Y Huang , Y He , X Sun , Y He , Y Li , C Sun . Maternal high folic acid supplement promotes glucose intolerance and insulin resistance in male mouse offspring fed a high-fat diet. Int J Mol Sci. 2014; 15, 62986313.

36. JC Wells . The thrifty phenotype as an adaptive maternal effect. Biol Rev Camb Philos Soc. 2007; 82, 143172.

37. SH Koo . Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis. Clin Mol Hepatol. 2013; 19, 210215.

38. ME D’Alessandro , ME Oliva , MA Fortino , A Chicco . Maternal sucrose-rich diet and fetal programming: changes in hepatic lipogenic and oxidative enzymes and glucose homeostasis in adult offspring. Food Funct. 2014; 5, 446453.

40. ML Ojeda , MJ Delgado-Villa , R Llopis , ML Murillo , O Carreras . Lipid metabolism in ethanol-treated rat pups and adults: effects of folic acid. Alcohol Alcohol. 2008; 43, 544550.

41. M Aragno , CE Tomasinelli , I Vercellinatto , et al. SREBP-1c in nonalcoholic fatty liver disease induced by western-type high-fat diet plus fructose in rats. Free Radic Biol Med. 2009; 47, 10671074.

42. MS Strable , JM Ntambi . Genetic control of de novo lipogenesis: role in diet-induced obesity. Crit Rev Biochem Mol Biol. 2010; 45, 199214.

44. S Majumder , K Ghoshal , J Datta , et al. Role of de novo DNA methyltransferases and methyl CpG-binding proteins in gene silencing in a rat hepatoma. J Biol Chem. 2002; 277, 1604816058.

45. RZ Jurkowska , TP Jurkowski , A Jeltsch . Structure and function of mammalian DNA methyltransferases. Chembiochem. 2011; 12, 206222.

46. L Gong , YX Pan , H Chen . Gestational low protein diet in the rat mediates Igf2 gene expression in male offspring via altered hepatic DNA methylation. Epigenetics. 2010; 5, 619626.

47. BQ Starley , CJ Calcagno , SA Harrison . Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010; 51, 18201832.

48. Y Kamei , T Suganami , T Ehara , et al. Increased expression of DNA methyltransferase 3a in obese adipose tissue: studies with transgenic mice. Obesity (Silver Spring). 2010; 18, 314321.

49. H Lu , JY Cui , S Gunewardena , B Yoo , XB Zhong , CD Klaassen . Hepatic ontogeny and tissue distribution of mRNAs of epigenetic modifiers in mice using RNA-sequencing. Epigenetics. 2012; 7, 914929.

50. P Cordero , FI Milagro , J Campion , JA Martinez . Maternal methyl donors supplementation during lactation prevents the hyperhomocysteinemia induced by a high-fat-sucrose intake by dams. Int J Mol Sci. 2013; 14, 2442224437.

51. SK Panchal , L Brown . Rodent models for metabolic syndrome research. J Biomed Biotechnol. 2011; 2011, 351982.

52. AP Garcia , M Palou , T Priego , J Sanchez , A Palou , C Pico . Moderate caloric restriction during gestation results in lower arcuate nucleus NPY- and alphaMSH-neurons and impairs hypothalamic response to fed/fasting conditions in weaned rats. Diabetes Obes Metab. 2010; 12, 403413.

53. A Gomez-Ruiz , FI Milagro , J Campion , JA Martinez , C de Miguel . High-fat diet feeding alters metabolic response to fasting/non fasting conditions. Effect on caveolin expression and insulin signalling. Lipids Health Dis.. 2011; 10, 55.

54. H Tsuchiya , Y Ikeda , Y Ebata , et al. Retinoids ameliorate insulin resistance in a leptin-dependent manner in mice. Hepatology. 2012; 56, 13191330.

55. E Tsiambas , SN Georgiannos , N Salemis , et al. Significance of estrogen receptor 1 (ESR-1) gene imbalances in colon and hepatocellular carcinomas based on tissue microarrays analysis. Med Oncol. 2011; 28, 934940.

56. JA Byrne , NJ Meara , AC Rayner , RJ Thompson , AS Knisely . Lack of hepatocellular CD10 along bile canaliculi is physiologic in early childhood and persistent in Alagille syndrome. Lab Invest. 2007; 87, 11381148.

Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Journal of Developmental Origins of Health and Disease
  • ISSN: 2040-1744
  • EISSN: 2040-1752
  • URL: /core/journals/journal-of-developmental-origins-of-health-and-disease
Please enter your name
Please enter a valid email address
Who would you like to send this to? *



Altmetric attention score

Full text views

Total number of HTML views: 3
Total number of PDF views: 30 *
Loading metrics...

Abstract views

Total abstract views: 139 *
Loading metrics...

* Views captured on Cambridge Core between September 2016 - 26th April 2017. This data will be updated every 24 hours.