Advertisement

Calcium-Deficient Diets in Pregnancy and Nursing: Epigenetic Change in Three Generations of Offspring

  • Junji Takaya
Reference work entry

Abstract

Prenatal malnutrition can affect the phenotype of offspring by changing epigenetic regulation. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. We previously reported that feeding a Ca-restricted diet to pregnant rats results in hypomethylation and decreased expression from the 11β-hydroxysteroid dehydrogenase-1 promoter in the liver of offspring at day 21. These findings show that a maternal Ca deficiency during pregnancy can affect the regulation of non-imprinted genes by altering the epigenetic regulation of gene expression, thereby inducing different metabolic phenotypes. The epigenome is an important target of environmental modification. In addition, we determined the effects of a Ca deficiency during pregnancy and/or lactation on insulin resistance and secretion in at least three generations. Female Wistar rats consumed either a Ca-deficient or control diet ad libitum from three weeks preconception to 21 days postparturition and were mated with control males. Randomly selected first (F1)- and second-generation (F2) females were mated with males of each generation on postnatal day 70. F1 and F2 dams were fed with a control diet ad libitum during pregnancy and lactation. On 180 days, homeostasis model assessment of beta cell function (HOMA-β%) gradually decreased in F1 through F3 and that in F2 and F3 males and females was significantly lower than control. These findings indicated that maternal Ca restriction during pregnancy and/or lactation influences insulin secretion in three generations of offspring.

Keywords

Calcium Glucocorticoid receptor HOMA-IR HOMA-β% Insulin resistance Metabolic syndrome Pregnancy Pyrosequencing Rat 11β-Hydroxysteroid dehydrogenase-1 

List of Abbreviations

Ca

Calcium

F1

First generation

F2

Second generation

F3

Third generation

GR

Glucocorticoid receptor

HOMA-IR

Homeostasis model assessment of insulin resistance

HOMA-β%

Homeostasis model assessment of beta cell function

11β-HSD1

11β-hydroxysteroid dehydrogenase-1

11β-HSD2

11β-hydroxysteroid dehydrogenase-2

Hsd11b1

11β-hydroxysteroid dehydrogenase-1 gene

Hsd11b2

11β-hydroxysteroid dehydrogenase-2 gene

Nr3c1

glucocorticoid receptor gene

PEPCK

phosphoenolpyruvate carboxykinase

Pck1

phosphoenolpyruvate carboxykinase gene

PPARα

peroxisome proliferator-activated receptor α

Ppara

rat peroxisome proliferator-activated receptor α gene

References

  1. Anagnostis P, Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis D (2009) The pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. J Clin Endocrinol Metab 94:2692–2701CrossRefGoogle Scholar
  2. Benyshek DC, Johnston CS, Martin JF (2008) Insulin sensitivity is normalized in the third generation (F3) offspring of developmentally programmed insulin resistant (F2) rats fed an energy-restricted diet. Nutr Metab (Lond) 5:26CrossRefGoogle Scholar
  3. Chaplin A, Palou A, Serra F (2017) Methylation analysis in fatty-acid related genes reveals their plasticity associated with conjugated acid and calcium supplementation in adult mice. Eur J Nutr 56:879–891Google Scholar
  4. Cooper MS, Stewart PM (2009) 11β-hydroxysteroid dehydrogenase type 1 and its role in the hypothalamus-pituitary-adrenal axis, metabolic syndrome, and inflammation. J Clin Endocrinol Metab 94:4645–4654CrossRefGoogle Scholar
  5. Dearden L, Balthasar N (2014) Sexual dimorphism in offspring glucose-sensitive hypothalamic Gene expression and physiological responses to maternal high-fat diet feeding. Endocrinology 155:2144–2154CrossRefGoogle Scholar
  6. Desai M, Byrne CD, Zhang J, Petry CJ, Lucas A, Hales CN (1997) Programming of hepatic insulin-sensitive enzymes in offspring of rat dams fed a protein-restricted diet. Am J Phys 272:G1083–G1090Google Scholar
  7. Draper N, Stewart PM (2005) 11β-hydroxysteroid dehydrogenase and the pre-receptor regulation of corticosteroid hormone action. J Endocrinol 186:251–271CrossRefGoogle Scholar
  8. Fu Q, Yu X, Callaway CW, Lane RH, McKnight RA (2009) Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene. FASEB J 23:2438–2449CrossRefGoogle Scholar
  9. Geer EB, Shen W (2009) Gender differences in insulin resistance, body composition, and energy balance. Gend Med 6(Suppl 1):60–75CrossRefGoogle Scholar
  10. Gong L, Pan YX, Chen H (2010) Gestational low protein diet in the rat mediates Igf2 gene expression in male offspring via altered hepatic DNA methylation. Epigenetics 5:619–626CrossRefGoogle Scholar
  11. Hall E, Volkov P, Tasnim Dayeh T, Esguerra JLS, Salö S et al (2014) Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets. Genome Biol 15:522CrossRefGoogle Scholar
  12. Hamo E, Cottrell EC, Keevil BG, DeSchoolmeester J, Bohlooly- YM et al (2013) 11-Dehydrocorticosterone causes metabolic syndrome, which is prevented when 11β-HSD1 is knocked out in livers of male mice. Endocrinology 154:3599–3609CrossRefGoogle Scholar
  13. Hanson RW, Patel YM (1994) Phosphoenolpyruvate carboxykinase (GTP) gene. Adv Enzymol Relat Areas Mol Biol 69:203–281PubMedGoogle Scholar
  14. Heard E, Martienssen RA (2014) Transgenerational epigenetic inheritance: myths and mechanisms. Cell 157:95–109CrossRefGoogle Scholar
  15. Hemanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M et al (2005) 11beta-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med 202:517–527CrossRefGoogle Scholar
  16. Hermans MP, Levy JC, Morris RJ, Turner RC (1999) Comparison of tests of beta-cell function across a range of glucose tolerance from normal to diabetes. Diabetes 48:1779–1786CrossRefGoogle Scholar
  17. Kaelin Jr WG, McKnight SL (2013) Influence of metabolism on epigenetics and disease. Cell 153:56–69CrossRefGoogle Scholar
  18. Lax ER, Ghraf R, Schriefers H (1978) The hormonal regulation of hepatic microsomal 11beta-hydroxtsteroid dehydrogenase activity in the rat. Acta Endocrinol 89:352–357CrossRefGoogle Scholar
  19. Lillycrop KA, Phillips ES, Torrens C, Hanson MA, Jackson AA, Burdge GC (2008) Feeding pregnant rats a protein-restricted diet persistently alters the methylation of specific cytosines in the hepatic PPAR alpha promoter of the offspring. Br J Nutr 100:278–282CrossRefGoogle Scholar
  20. Lillycrop KA, Phillips ES, Jackson AA, Hanson MA, Burdge GC (2005) Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr 135:1382–1386CrossRefGoogle Scholar
  21. Lindsay RS, Wake DJ, Nair S, Bunt J, Livingstone DE et al (2003) Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in pima Indians and Caucasians. J Clin Endocrinol Metab 88:2738–2744CrossRefGoogle Scholar
  22. Liu S, Song Y, Ford ES, Manson JE, Buring JE, Ridker PM (2005) Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care 28:2926–2932CrossRefGoogle Scholar
  23. Liu Y, Nakagawa Y, Wang Y, Li R, Li X et al (2003) Leptin activation of corticosterone production in hepatocytes may contribute to the reversal of obesity and hyperglycemia in leptin-deficient ob/ob mice. Diabetes 52:1409–1416CrossRefGoogle Scholar
  24. Livingstone DE, Jones GC, Smith K, Jamieson PM, Andrew R et al (2001) Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats. Endocrinology 141:560–563CrossRefGoogle Scholar
  25. Macotela Y, Boucher J, Tran TT, Kahn CR (2009) Sex and depot differences in adipocyte insulin sensitivity and glucose metabolism. Diabetes 58:803–812CrossRefGoogle Scholar
  26. Masuzaki H, Yamamoto H, Kenyon CJ, Elmquist JK, Morton NM, Paterson JM, Shinyama H, Sharp MG, Fleming S, Mullins JJ, Seckl JR, Flier JS (2003) Transgenic amplification of glucocorticoid action in adipose tissue causes high blood pressure in mice. J Clin Invest 112:83–90CrossRefGoogle Scholar
  27. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419CrossRefGoogle Scholar
  28. Morgan SA, McCabe EL, Gathercole LL, Hassan-Smith ZK, Larner DP et al (2014) 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess. Proc Natl Acad Sci USA 111:E2482–E2491Google Scholar
  29. Morton NM, Seckl JR (2008) 11beta-hydroxysteroid dehydrogenase type 1 and obesity. Front Horm Res 36:146–164CrossRefGoogle Scholar
  30. Ng SF, Lin RC, Laybutt DR, Barres R, Owens JA et al (2010) Chronic high-fat diet in fathers programs ß-cell dysfunction in female rat offspring. Nature 467:963–966CrossRefGoogle Scholar
  31. Patel MS, Srinivasan M (2011) Metabolic programming in the immediate postnatal life. Ann Nutr Metab 58(Suppl 2):18–28CrossRefGoogle Scholar
  32. Paulmyer-Lacrox O, Boullu S, Oliver C, Alessi MC, Grino M (2002) Expression of the mRNA coding for 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study. J Clin Endocrinol Metab 87:2701–2705Google Scholar
  33. Pereira MA, Jacobs DRJ, Van Horn L, Slattery ML, Kartashov AI, Ludwig DS (2002) Dairy consumption, obesity, and the insulin resistance syndrome in young adults: the CARDIA study. JAMA 287:2081–2089CrossRefGoogle Scholar
  34. Pikilidou MI, Lasaridis AN, Sarafidis PA et al (2009) Insulin sensitivity increase after calcium supplementation and change in intraplatelet calcium and sodium-hydrogen exchange in hypertensive patients with type 2 diabetes. Diabetes Med 26:211–219CrossRefGoogle Scholar
  35. Pittas AG, Lau J, FB H, Dawson-Hughes B (2007) The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab 92:2017–2029CrossRefGoogle Scholar
  36. Rask E, Olsson T, Sodenberg S, Andrew R, Livingstone DE et al (2001) Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86:1418–1421CrossRefGoogle Scholar
  37. Schrager S (2005) Dietary calcium intake and obesity. J Am Board Fam Pract 18:205–210CrossRefGoogle Scholar
  38. Skinner MK (2008) What is an epigenetic transgenerational phenotype? F3 or F2. Reprod Toxicol 25:2–6CrossRefGoogle Scholar
  39. Srinivasan M, Mahmood S, Patel MS (2013) Metabolic programming effects initiated in the suckling period predisposing for adult-onset obesity cannot be reversed by calorie restriction. Am J Physiol Endocrinol Metab 304:E486–E494CrossRefGoogle Scholar
  40. Takaya J, Yamanouchi S, Tanabe Y, Kaneko K (2016) A calcium-deficient diet in rat dams during gestation decreases HOMA-β% in 3 generations of offspring. J Nutrigenet Nutrigenomics 9:276–286Google Scholar
  41. Takaya J, Yamanouchi S, Kaneko K (2014) A calcium-deficient diet in rat dams during gestation and nursing affects hepatic 11β-hydroxysteroid dehydrogenase-1 expression in the offspring. PLoS One 9:e84125CrossRefGoogle Scholar
  42. Takaya J, Iharada A, Okihana H, Kaneko K (2013) A calcium-deficient diet in pregnant, nursing rats induces hypomethylation of specific cytosines in the 11β-hydroxysteroid dehydrogenase-1 promoter in pup liver. Nutr Res 33:961–970CrossRefGoogle Scholar
  43. Takaya J, Iharada A, Okihana H, Kaneko K (2011) Upregulation of hepatic 11β-hydroxysteroid dehydrogenase-1 expression in calcium-deficient rats. Ann Nutr Metab 59:73–78CrossRefGoogle Scholar
  44. Tomlinson JW, Walker EA, Bujalska IJ, Draper N, Lavery GG, Cooper MS, Hewison M, Stewart PM (2004) 11β-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response. Endocr Rev 25:831–866CrossRefGoogle Scholar
  45. Valdez R, Athens MA, Thompson GH, Bradshaw BS, Stem MP (1994) Birthweight and adult health outcomes in a biethnic population in the USA. Diabetologia 37:624–631CrossRefGoogle Scholar
  46. Walker BR (2006) Cortisol—cause and cure for metabolic syndrome? Diabet Med 23:1281–1288CrossRefGoogle Scholar
  47. Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27:1487–1495CrossRefGoogle Scholar
  48. Warner MJ, Ozanne SE (2010) Mechanisms involved in the developmental programming of adulthood disease. Biochem J 427:333–347CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of PediatricsKawachi General HospitalHigashi-OsakaJapan
  2. 2.Department of PediatricsKansai Medical UniversityMoriguchiJapan

Personalised recommendations