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Maternal restraint stress during pregnancy in mice induces 11β-HSD1-associated metabolic changes in the livers of the offspring

Part of: Epigenetics as the Mediator of the Gene/Environment Interactions in DOHAD

Published online by Cambridge University Press:  24 February 2015

H. Maeyama ,
T. Hirasawa ,
Y. Tahara ,
C. Obata ,
H. Kasai ,
K. Moriishi ,
K. Mochizuki  and
T. Kubota
H. Maeyama
Affiliation:
Department of Epigenetic Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
T. Hirasawa*
Affiliation:
Department of Epigenetic Medicine, University of Yamanashi, Chuo, Yamanashi, Japan Japan Science and Technology Agency (JST), CREST, Kawaguchi, Saitama, Japan
Y. Tahara
Affiliation:
Department of Epigenetic Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
C. Obata
Affiliation:
Department of Epigenetic Medicine, University of Yamanashi, Chuo, Yamanashi, Japan Japan Science and Technology Agency (JST), CREST, Kawaguchi, Saitama, Japan
H. Kasai
Affiliation:
Department of Microbiology, University of Yamanashi, Chuo, Yamanashi, Japan
K. Moriishi
Affiliation:
Department of Microbiology, University of Yamanashi, Chuo, Yamanashi, Japan
K. Mochizuki
Affiliation:
Faculty of Life and Environmental Sciences, University of Yamanashi, Kofu, Yamanashi, Japan
T. Kubota
Affiliation:
Department of Epigenetic Medicine, University of Yamanashi, Chuo, Yamanashi, Japan
*
*Address for correspondence: T. Hirasawa, Department of Epigenetic Medicine, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan. (Email takae@yamanashi.ac.jp)
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Abstract

In rats, maternal exposure to restraint stress during pregnancy can induce abnormalities in the cardiovascular and central nervous systems of the offspring. These effects are mediated by long-lasting hyperactivation of the hypothalamic–pituitary–adrenal axis. However, little is known about the potential effects of stress during pregnancy on metabolic systems. We examined the effect of restraint stress in pregnant mice on the liver function of their offspring. The offspring of stressed mothers showed significantly higher lipid accumulation in the liver after weaning than did the controls; this accumulation was associated with increased expression of lipid metabolism-related proteins such as alanine aminotransferase 2 diglyceride acyltransferase 1, peroxisome proliferator-activated receptor gamma and glucocorticoid receptor. Additionally, we observed increased levels of 11β-hydroxysteroid dehydrogenase type 1, an intercellular mediator that converts glucocorticoid from the inactive to the active form, in the foetal and postnatal periods. These results indicate that restraint stress in pregnancy in mice induces metabolic abnormalities via 11β-hydroxysteroid dehydrogenase type 1-related pathways in the foetal liver. It is therefore possible that exposure to stress in pregnant women may be a risk factor for metabolic syndromes (e.g. fatty liver) in children.

Keywords

fatty livermetabolic syndromepregnancyrestraint stress11β-HSD1

Information

Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 6 , Supplement 2 , April 2015 , pp. 105 - 114
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Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2015 

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References

1. Godfrey, KM, Barker, DJ. Fetal programming and adult health. Public Health Nutr. 2001; 4, 611–624.CrossRefGoogle ScholarPubMed
2. Gluckman, PD, Hanson, MA. Living with the past: evolution, development, and patterns of disease. Science. 2004; 305, 1733–1736.CrossRefGoogle ScholarPubMed
3. Gluckman, PD, Seng, CY, Fukuoka, H, Beedle, AS, Hanson, MA. Low birthweight and subsequent obesity in Japan. Lancet. 2007; 369, 1081–1082.CrossRefGoogle ScholarPubMed
4. Painter, RC, de Rooij, SR, Bossuyt, PM, et al. Early onset of coronary artery disease after prenatal exposure to the Dutch famine. Am J Clin Nutr. 2006; 84, 322–327.CrossRefGoogle Scholar
5. St Clair, D, Xu, M, Wang, P, et al. Rates of adult schizophrenia following prenatal exposure to the Chinese famine of 1959–1961. JAMA. 2005; 294, 557–562.CrossRefGoogle Scholar
6. Barker, DJ. The origins of the developmental origins theory. J Intern Med. 2007; 261, 412–417.CrossRefGoogle ScholarPubMed
7. Silveira, PP, Portella, AK, Goldani, MZ, Barbieri, MA. Developmental origins of health and disease (DOHaD). Jornal de Pediatria. 2007; 83, 494–504.CrossRefGoogle ScholarPubMed
8. Darnaudéry, M, Maccari, S. Epigenetic programming of the stress response in male and female rats by prenatal restraint stress. Brain Res Rev. 2008; 57, 571–585.CrossRefGoogle ScholarPubMed
9. Igosheva, N, Klimova, O, Anishchenko, T, Glover, V. Prenatal stress alters cardiovascular responses in adult rats. J Physiol. 2004; 557, 273–285.CrossRefGoogle ScholarPubMed
10. Igosheva, N, Taylor, PD, Poston, L, Glover, V. Prenatal stress in the rat results in increased blood pressure responsiveness to stress and enhanced arterial reactivity to neuropeptide Y in adulthood. J Physiol. 2007; 582(Pt 2), 665–674.CrossRefGoogle ScholarPubMed
11. Viltart, O, Mairesse, J, Darnaudéry, M, et al. Prenatal stress alters Fos protein expression in hippocampus and locus coeruleus stress-related brain structures. Psychoneuroendocrinology. 2006; 31, 769–780.CrossRefGoogle ScholarPubMed
12. Morley-Fletcher, S, Darnaudéry, M, Mocaer, E, et al. Chronic treatment with imipramine reverses immobility behaviour, hippocampal corticosteroid receptors and cortical 5-HT(1A) receptor mRNA in prenatally stressed rats. Neuropharmacology. 2004; 47, 841–847.CrossRefGoogle ScholarPubMed
13. Li, J, Olsen, J, Vestergaard, M, et al. Prenatal stress exposure related to maternal bereavement and risk of childhood overweight. PLoS One. 2010; 5, e11896.CrossRefGoogle ScholarPubMed
14. Paterson, JM, Morton, NM, Fievet, C, et al. Metabolic syndrome without obesity: hepatic overexpression of 11 beta-hydroxysteroid dehydrogenase type 1 in transgenic mice. PNAS. 2004; 101, 7088–7093.CrossRefGoogle ScholarPubMed
15. Gandhi, K, Adhikari, P, Basu, A, Achappa, B. Association between a 11β-hydroxysteroid dehydrogenase type 1 gene polymorphism and metabolic syndrome in a South Indian population. Metab Syndr Relat Disord. 2013; 11, 397–402.CrossRefGoogle Scholar
16. Moon, SS, Lee, YS, Kim, JG, Lee, IK. Association of 11β-hydroxysteroid dehydrogenase type 1 gene polymorphisms with serum alanine aminotransferase activity. Diabetes Res Clin Pr. 2013; 99, 343–350.CrossRefGoogle ScholarPubMed
17. Fujisawa, Y, Nakagawa, Y, Li, RS, Liu, YJ, Ohzeki, T. Diabetic pregnancy in rats leads to impaired glucose metabolism in offspring involving tissue-specific dysregulation of 11 beta-hydroxysteroid dehydrogenase type 1 expression. Life Sci. 2007; 81, 724–731.CrossRefGoogle Scholar
18. McTernan, CL, Draper, N, Nicholson, H, et al. Reduced placental 11 beta hydroxysteroid dehydrogenase type2 mRNA levels in human pregnancies complicated by intrauterine growth restriction: an analysis of possible mechanisms. J Clin Endocrinol Metab. 2001; 86, 4979–4983.Google Scholar
19. Takaya, J, Iharada, A, Okihana, H, Kaneko, K. Magnesium deficiency in pregnant rats alters methylation of specific cytosines in the hepatic hydroxysteroid dehydrogenase-2 promoter of the offspring. Epigenetics. 2011; 6, 573–578.CrossRefGoogle ScholarPubMed
20. Morton, NM, Holmes, MC, Fiévet, C, et al. Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11 beta-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem. 2001; 276, 41293–41300.CrossRefGoogle ScholarPubMed
21. Morton, NM, Paterson, JM, Masuzaki, H, et al. Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes. 2004; 53, 931–938.CrossRefGoogle ScholarPubMed
22. Anderson, A, Walker, BR. 11β-HSD1 inhibitors for the treatment of type 2 diabetes and cardiovascular disease. Drugs. 2013; 73, 1385–1393.CrossRefGoogle ScholarPubMed
23. Harno, E, Cottrell, EC, Yu, A, et al. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitors still improve metabolic phenotype in male 11β-HSD1 knockout mice suggesting off-target mechanisms. Endocrinology. 2013; 154, 4580–4593.CrossRefGoogle ScholarPubMed
24. Matsusue, K, Haluzik, M, Lambert, G, et al. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest. 2003; 111, 737–747.CrossRefGoogle ScholarPubMed
25. Masuzaki, H, Paterson, J, Shinyama, H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001; 294, 2166–2170.CrossRefGoogle ScholarPubMed
26. Liu, Y, Park, F, Pietrusz, JL, et al. Suppression of 11beta-hydroxysteroid dehydrogenase type 1 with RNA interference substantially attenuates 3T3-L1 adipogenesis. Physiol Genom. 2008; 32, 343–351.CrossRefGoogle ScholarPubMed
27. Berthiaume, M, Laplante, M, Festuccia, W, et al. Depot-specific modulation of rat intraabdominal adipose tissue lipid metabolism by pharmacological inhibition of 11beta-hydroxysteroid dehydrogenase type 1. Endocrinology. 2007; 148, 2391–2397.CrossRefGoogle ScholarPubMed
28. Arai, K, Soga, T, Ohata, H, et al. Effects of food restriction on peroxisome proliferator-activated receptor-gamma and glucocorticoid receptor signaling in adipose tissues of normal rats. Metabolism. 2004; 53, 28–36.CrossRefGoogle ScholarPubMed
29. Rhee, SD, Kim, CH, Park, JS, et al. Carbenoxolone prevents the development of fatty liver in C57BL/6-Lep ob/ob mice via the inhibition of sterol regulatory element binding protein-1c activity and apoptosis. Eur J Pharmacol. 2012; 691, 9–18.CrossRefGoogle ScholarPubMed
30. Lillycrop, KA, Phillips, ES, Jackson, AA, Hanson, MA, Burdge, GC. Dietary protein restriction of pregnant rats induces and folic acid supplementation prevents epigenetic modification of hepatic gene expression in the offspring. J Nutr. 2005; 135, 1382–1386.CrossRefGoogle ScholarPubMed
31. Lillycrop, KA, Phillips, ES, Torrens, C, et al. 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. 2008; 100, 278–282.CrossRefGoogle ScholarPubMed
32. Chapman, K, Holmes, M, Seckl, J. 11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. Physiol Rev. 2013; 93, 1139–1206.CrossRefGoogle ScholarPubMed
33. Torrecilla, E, Fernández-Vázquez, G, Vicent, D, et al. Liver upregulation of genes involved in cortisol production and action is associated with metabolic syndrome in morbidly obese patients. Obesity Surg. 2012; 22, 478–486.CrossRefGoogle ScholarPubMed
34. Ahmed, A, Rabbitt, E, Brady, T, et al. A switch in hepatic cortisol metabolism across the spectrum of non-alcoholic fatty liver disease. PLoS One. 2012; 7, e29531.CrossRefGoogle ScholarPubMed
35. Rueda-Clausen, CF, Dolinsky, VW, Morton, JS, et al. Hypoxia-induced intrauterine growth restriction increases the susceptibility of rats to high-fat diet-induced metabolic syndrome. Diabetes. 2011; 60, 507–516.CrossRefGoogle ScholarPubMed
36. Nobili, V, Alisi, A, Panera, N, Agostoni, C. Low birth weight and catch-up-growth associated with metabolic syndrome: a ten year systematic review. Ped Endocrinol Rev. 2008; 6, 241–247.Google Scholar
37. Alisi, A, Panera, N, Agostoni, C, Nobili, V. Intrauterine growth retardation and nonalcoholic fatty liver disease in children. Int J Endocrinol. 2011; 269853.Google ScholarPubMed
38. Nobili, V, Alisi, A, Grimaldi, C, et al. Non-alcoholic fatty liver disease and hepatocellular carcinoma in a 7-year-old obese boy: coincidence or comorbidity? Pediatr Obes. 2014; 9, e99–e102.CrossRefGoogle ScholarPubMed
39. Andrews, RC, Rooyackers, O, Walker, BR. Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab. 2003; 88, 285–291.CrossRefGoogle ScholarPubMed
40. Vicker, N, Su, X, Ganeshapillai, D, et al. Novel non-steroidal inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1. J Steroid Biochem Mol Biol. 2007; 104, 123–129.CrossRefGoogle ScholarPubMed
41. Kim, JG, Jung, HS, Kim, KJ, Min, SS, Yoon, BJ. Basal blood corticosterone level is correlated with susceptibility to chronic restraint stress in mice. Neurosci Lett. 2013; 555, 137–142.CrossRefGoogle ScholarPubMed
42. Mairesse, J, Lesage, J, Breton, C, et al. Maternal stress alters endocrine function of the feto-placental unit in rats. Am J Physiol Endocrinol Metab. 2007; 292, E1526–E1533.CrossRefGoogle ScholarPubMed
43. Hollis, G, Huber, R. 11β-Hydroxysteroid dehydrogenase type 1 inhibition in type 2 diabetes mellitus. Diabetes Obes Metab. 2011; 13, 1–6.CrossRefGoogle ScholarPubMed
44. Andrews, RC, Walker, BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci. 1999; 96, 513–523.CrossRefGoogle ScholarPubMed
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