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Neurochemical Research

, Volume 33, Issue 4, pp 624–636 | Cite as

11β-HSD1, Inflammation, Metabolic Disease and Age-related Cognitive (dys)Function

Original Paper

Abstract

11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an intracellular amplifier of glucocorticoid action. By converting intrinsically inert glucocorticoids (cortisone, 11-dehydrocorticosterone) into their active forms (cortisol, corticosterone), 11β-HSD1 increases glucocorticoid access to receptors. Glucocorticoid hormones modulate diverse physiological processes, linking circadian rhythms to food seeking, motivational and cognitive behaviours, as well as intermediary metabolism and immune responses. They are a key component of pathways that buffer the organism against stressful challenges. Here we review the part played in these processes by 11β-HSD1, and discuss the promise of inhibitors of 11β-HSD1 in alleviating disorders associated with cumulative stress.

Keywords

Steroid metabolism Glucocorticoid 11β-HSD1 

Notes

Acknowledgements

We would like to thank members of the Endocrinology Unit, QMRI, for many stimulating discussions on all aspects of glucocorticoid metabolism and action. Work in the authors’ laboratories is funded by grants from the Wellcome Trust, the Scottish Hospitals Endowments Research Trust, the Medical Research Council, the British Heart Foundation, the Leukaemia Research Fund and the European Union.

References

  1. 1.
    McEwen BS (2003) Interacting mediators of allostasis and allostatic load: towards an understanding of resilience in aging. Metabolism 52:10–16PubMedGoogle Scholar
  2. 2.
    Vanderbilt JN, Miesfeld R, Maler BA, Yamamoto KR (1987) Intracellular receptor concentration limits glucocorticoid-dependent enhancer activity. Mol Endocrinol 1:68–74PubMedGoogle Scholar
  3. 3.
    Ramdas J, Liu W, Harmon JM (1999) Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. Cancer Res 59:1378–1385PubMedGoogle Scholar
  4. 4.
    Reichardt HM, Umland T, Bauer A, Kretz O, Schütz G (2000) Mice with an increased glucocorticoid receptor gene dosage show enhanced resistance to stress and endotoxic shock. Mol Cell Biol 20:9009–9017PubMedGoogle Scholar
  5. 5.
    Robyr D, Wolffe AP, Wahli W (2000) Nuclear hormone receptor coregulators in action: diversity for shared tasks. Mol Endocrinol 14:329–347PubMedGoogle Scholar
  6. 6.
    Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM (2001) Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. Nature 413:131–138PubMedGoogle Scholar
  7. 7.
    McEwen BS (1992) Steroid hormones: effect on brain development and function. Horm Res 37:1–10PubMedGoogle Scholar
  8. 8.
    Dallman MF, Strack AM, Akana SF, Bradbury MJ, Hanson ES, Scribner KA, Smith M (1993) Feast and famine: critical role of glucocorticoids with insulin in daily energy flow. Front Neuroendocrinol 14:303–347PubMedGoogle Scholar
  9. 9.
    McEwen BS, Biron CA, Brunson KW, Bulloch K, Chambers WH, Dhabhar FS, Goldfarb RH, Kitson RP, Miller AH, Spencer RL, Weiss JM (1997) The role of adrenocorticoids as modulators of immune function in health and disease: neural, endocrine and immune interactions. Brain Res Rev 23:79–133PubMedGoogle Scholar
  10. 10.
    Manary MJ, Muglia LJ, Vogt SK, Yarasheski KE (2006) Cortisol and its action on the glucocorticoid receptor in malnutrition and acute infection. Metabolism 55:550–554PubMedGoogle Scholar
  11. 11.
    Oelkers W (1996) Adrenal insufficiency. N Engl J Med 335:1206–1212PubMedGoogle Scholar
  12. 12.
    Dougherty TF, Schneebeli GL (1955) The use of steroids as anti-inflammatory agents. Ann N Y Acad Sci 61:328–348PubMedGoogle Scholar
  13. 13.
    Bertini R, Bianchi M, Ghezzi P (1988) Adrenalectomy sensitizes mice to the lethal effects of interleukin-1 and tumor necrosis factor. J Exp Med 167:1708–1712PubMedGoogle Scholar
  14. 14.
    McEwen BS (1999) Stress and the aging hippocampus. Front Neuroendocrinol 20:49–70PubMedGoogle Scholar
  15. 15.
    McEwen BS (2003) Mood disorders and allostatic load. Biol Psychiatr 54:200–207Google Scholar
  16. 16.
    Sloviter RS, Valiquette G, Abrams GM, Ronk EC, Sollas AL, Paul LA, Neubort S (1989) Selective loss of hippocampal granule cells in the mature rat-brain after adrenalectomy. Science 243:535–538PubMedGoogle Scholar
  17. 17.
    Derijk R, de Kloet ER (2005) Corticosteroid receptor genetic polymorphisms and stress responsivity. Endocrine 28:263–270PubMedGoogle Scholar
  18. 18.
    Seckl JR (2001) Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Mol Cell Endocrinol 185:61–71PubMedGoogle Scholar
  19. 19.
    Yehuda R, Engel SM, Brand SR, Seckl J, Marcus SM, Berkowitz GS (2005) Transgenerational effects of posttraumatic stress disorder in babies of mothers exposed to the World Trade Center attacks during pregnancy. J Clin Endocrinol Metab 90:4115–4118PubMedGoogle Scholar
  20. 20.
    Meaney MJ, Aitken DH, van Berkel C, Bhatnagar S, Sapolsky RM (1988) Effect of neonatal handling on age-related impairments associated with the hippocampus. Science 239:766–768PubMedGoogle Scholar
  21. 21.
    Shanks N, Windle RJ, Perks PA, Harbuz MS, Jessop DS, Ingram CD, Lightman SL (2000) Early-life exposure to endotoxin alters hypothalamic–pituitary–adrenal function and predisposition to inflammation. Proc Natl Acad Sci USA 97:5645–5650PubMedGoogle Scholar
  22. 22.
    Francis D, Diorio J, Liu D, Meaney MJ (1999) Nongenomic transmission across generations of maternal behavior and stress responses in the rat. Science 286:1155–1158PubMedGoogle Scholar
  23. 23.
    Drake AJ, Walker BR, Seckl JR (2005) Intergenerational consequences of fetal programming by in utero exposure to glucocorticoids in rats. Am J Physiol Regul Integr Comp Physiol 288:R34–38PubMedGoogle Scholar
  24. 24.
    Amelung D, Hubener HJ, Roka L, Meyerheim G (1953) Conversion of cortisone to compound F. J Clin Endocrinol Metab 13:1125–1126PubMedGoogle Scholar
  25. 25.
    Stewart PM, Krozowski ZS (1999) 11β-hydroxysteroid dehydrogenase. Vitam Horm 57:249–324PubMedGoogle Scholar
  26. 26.
    Seckl JR (2004) 11β-hydroxysteroid dehydrogenases: changing glucocorticoid action. Curr Opin Pharmacol 4:597–602PubMedGoogle Scholar
  27. 27.
    Brown RW, Chapman KE, Edwards CRW, Seckl JR (1993) Human placental 11β-hydroxysteroid dehydrogenase: partial purification of and evidence for a distinct NAD-dependent isoform. Endocrinology 132:2614–2621PubMedGoogle Scholar
  28. 28.
    Brown RW, Chapman KE, Edwards CRW, Seckl JR (1996) Purification of 11β-hydroxysteroid dehydrogenase type 2 from human placenta. Biochem J 313:997–1005PubMedGoogle Scholar
  29. 29.
    Albiston AL, Obeyesekere VR, Smith RE, Krozowski ZS (1994) Cloning and tissue distribution of the human 11β-hydroxysteroid dehydrogenase type 2 enzyme. Mol Cell Endocrinol 105:R11–R17PubMedGoogle Scholar
  30. 30.
    Cole TJ (1995) Cloning of the mouse 11β-hydroxysteroid dehydrogenase type 2 gene: tissue-specific expression and localization in distal convoluted tubules and collecting ducts of the kidney. Endocrinology 136:4693–4696PubMedGoogle Scholar
  31. 31.
    Brown RW, Chapman KE, Kotelevtsev Y, Yau JLW, Lindsay RS, Brett L, Leckie C, Murad P, Lyons V, Mullins JJ, Edwards CRW, Seckl JR (1996) Cloning and production of antisera to human placental 11β-hydroxysteroid dehydrogenase type 2. Biochem J 313:1007–1017PubMedGoogle Scholar
  32. 32.
    Edwards CRW, Stewart PM, Burt D, Brett L, McIntyre MA, Sutanto WS, de Kloet ER, Monder C (1988) Localisation of 11β-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor. Lancet ii:986–989Google Scholar
  33. 33.
    Funder JW, Pearce PT, Smith R, Smith AI (1988) Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 242:583–585PubMedGoogle Scholar
  34. 34.
    Brown RW, Diaz R, Robson AC, Kotolevtsev Y, Mullins JJ, Kaufman MH, Seckl JR (1996) The ontogeny of 11β-hydroxysteroid dehydrogenase type 2 and mineralocorticoid receptor gene expression reveal intricate control of glucocorticoid action in development. Endocrinology 137:794–797PubMedGoogle Scholar
  35. 35.
    Seckl JR, Cleasby M, Nyirenda MJ (2000) Glucocorticoids, 11β-hydroxysteroid dehydrogenase, and fetal programming. Kidney Int 57:1412–1417PubMedGoogle Scholar
  36. 36.
    Seckl JR (1995) The syndrome of Apparent Mineralocorticoid Excess and deficiency of 11β-hydroxysteroid dehydrogenase. Clin Endocrinol 43:247–248Google Scholar
  37. 37.
    Mune T, Rogerson FM, Nikkila H, Agarwal AK, White PC (1995) Human hypertension caused by mutations in the kidney isozyme of 11β-hydroxysteroid dehydrogenase. Nat Genet 10:394–399PubMedGoogle Scholar
  38. 38.
    Kotelevtsev Y, Brown RW, Fleming S, Kenyon C, Edwards CRW, Seckl JR, Mullins JJ (1999) Hypertension in mice lacking 11β-hydroxysteroid dehydrogenase type 2. J Clin Invest 103:683–689PubMedGoogle Scholar
  39. 39.
    Holmes MC, Abrahamsen CT, French KL, Paterson JM, Mullins JJ, Seckl JR (2006) The mother or the fetus? 11β-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. J Neurosci 26:3840–3844PubMedGoogle Scholar
  40. 40.
    Holmes MC, Sangra M, French KL, Whittle IR, Paterson J, Mullins JJ, Seckl JR (2006) 11β-hydroxysteroid dehydrogenase type 2 protects the neonatal cerebellum from deleterious effects of glucocorticoids. Neuroscience 137:865–873PubMedGoogle Scholar
  41. 41.
    Ulick S, Levine LS, Gunczler P, Zanconato G, Ramirez LC, Rauh W, Rosler A, Bradlow HL, New MI (1979) A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J Clin Endocrinol Metab 49:757–764PubMedGoogle Scholar
  42. 42.
    Duperrex H, Kenouch S, Gaeggeler H-P, Seckl JR, Edwards CRW, Farman N, Rossier BC (1993) Rat liver 11β-hydoxysteroid dehydrogenase cDNA encodes oxoreductase activity in a mineralocorticoid-responsive toad bladder cell line. Endocrinology 132:612–619PubMedGoogle Scholar
  43. 43.
    Low SC, Chapman KE, Edwards CRW, Seckl JR (1994) ‘Liver-type’ 11β-hydroxysteroid dehydrogenase cDNA encodes reductase not dehydrogenase activity in intact mammalian COS-7 cells. J Mol Endocrinol 13:167–174PubMedGoogle Scholar
  44. 44.
    Jamieson PM, Chapman KE, Edwards CRW, Seckl JR (1995) 11β-hydroxysteroid dehydrogenase is an exclusive 11β-reductase in primary cultures of rat hepatocytes: effect of physicochemical and hormonal manipulations. Endocrinology 136:4754–4761PubMedGoogle Scholar
  45. 45.
    Bujalska IJ, Kumar S, Stewart PM (1997) Does central obesity reflect “Cushing’s disease of the omentum”? Lancet 349:1210–1213PubMedGoogle Scholar
  46. 46.
    Napolitano A, Voice MW, Edwards CRW, Seckl JR, Chapman KE (1998) 11β-hydroxysteroid dehydrogenase 1 in adipocytes: expression is differentiation-dependent and hormonally regulated. J Steroid Biochem Molec Biol 64:251–260PubMedGoogle Scholar
  47. 47.
    Walker BR, Campbell JC, Fraser R, Stewart PM, Edwards CRW (1992) Mineralocorticoid excess and inhibition of 11β-hydroxysteroid dehydrogenase in patients with ectopic ACTH syndrome. Clin Endocrinol 37:483–492Google Scholar
  48. 48.
    Ozols J (1995) Lumenal orientation and posttranslational modifications of the liver microsomal 11β-hydroxysteroid dehydrogenase. J Biol Chem 270:2305–2312PubMedGoogle Scholar
  49. 49.
    Atanasov AG, Nashev LG, Schweizer RA, Frick C, Odermatt A (2004) Hexose-6-phosphate dehydrogenase determines the reaction direction of 11β-hydroxysteroid dehydrogenase type 1 as an oxoreductase. FEBS Lett 571:129–133PubMedGoogle Scholar
  50. 50.
    Banhegyi G, Benedetti A, Fulceri R, Senesi S (2004) Cooperativity between 11β-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase in the lumen of the endoplasmic reticulum. J Biol Chem 279:27017–27021PubMedGoogle Scholar
  51. 51.
    Bujalska IJ, Draper N, Michailidou Z, Tomlinson JW, White PC, Chapman KE, Walker EA, Stewart PM (2005) Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11β-hydroxysteroid dehydrogenase type 1. J Mol Endocrinol 34:675–684PubMedGoogle Scholar
  52. 52.
    Lavery GG, Chalder SM, Walker EA, Stewart PM (2006) ‘Apparent Cortisone Reductase Deficiency’ is a monogenic disorder caused by mutations in hexose-6-phosphate dehydrogenase. In: Abstracts of the 88th meeting of the American Endocrine Society OR50-1Google Scholar
  53. 53.
    Lavery GG, Walker EA, Draper N, Jeyasuria P, Marcos J, Shackleton CH, Parker KL, White PC, Stewart PM (2006) Hexose-6-phosphate dehydrogenase knock-out mice lack 11β-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation. J Biol Chem 281:6546–6551PubMedGoogle Scholar
  54. 54.
    Agarwal AK, Monder C, Eckstein B, White PC (1989) Cloning and expression of rat cDNA encoding corticosteroid 11β-dehydrogenase. J Biol Chem 264:18939–18943PubMedGoogle Scholar
  55. 55.
    Tannin GM, Agarwal AK, Monder C, New MI, White PC (1991) The human gene for 11β-hydroxysteroid dehydrogenase. J Biol Chem 266:16653–16658PubMedGoogle Scholar
  56. 56.
    Moisan M-P, Seckl JR, Brett LP, Monder C, Agarwal AK, White PC, Edwards CRW (1990) 11β-hydroxysteroid dehydrogenase messenger ribonuceic acid expression, bioactivity and immunoreactivity in rat cerebellum. J Neuroendocrinol 2:853–858PubMedGoogle Scholar
  57. 57.
    Moisan M-P, Seckl JR, Edwards CRW (1990) 11β-hydroxysteroid dehydrogenase bioactivity and messenger RNA expression in rat forebrain: localization in hypothalamus, hippocampus and cortex. Endocrinology 127:1450–1455PubMedGoogle Scholar
  58. 58.
    Whorwood CB, Franklyn JA, Sheppard MC, Stewart PM (1992) Tissue localisation of 11β-hydroxysteroid dehydrogenase and its relationship to the glucocorticoid receptor. J Steroid Biochem Mol Biol 41:21–28PubMedGoogle Scholar
  59. 59.
    Thieringer R, Le Grand CB, Carbin L, Cai TQ, Wong B, Wright SD, Hermanowski-Vosatka A (2001) 11β-Hydroxysteroid dehydrogenase type 1 is induced in human monocytes upon differentiation to macrophages. J Immunol 167:30–35PubMedGoogle Scholar
  60. 60.
    Zhang TY, Ding X, Daynes RA (2005) The expression of 11β-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities. J Immunol 174:879–889PubMedGoogle Scholar
  61. 61.
    Gilmour JS, Coutinho AE, Cailhier JF, Man TY, Clay M, Thomas G, Harris HJ, Mullins JJ, Seckl JR, Savill JS, Chapman KE (2006) Local amplification of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes. J Immunol 176:7605–7611PubMedGoogle Scholar
  62. 62.
    Stewart PM, Boulton A, Kumar S, Clark PMS, Shackleton CHL (1999) Cortisol metabolism in human obesity: impaired cortisone->cortisol conversion in subjects with central adiposity. J Clin Endocrinol Metab 84:1022–1027PubMedGoogle Scholar
  63. 63.
    Rask E, Olsson T, Söderberg S, Andrew R, Livingstone DE, Johnson O, Walker BR (2001) Tissue-specific dysregulation of cortisol metabolism in human obesity. J Clin Endocrinol Metab 86:1418–1421PubMedGoogle Scholar
  64. 64.
    Rask E, Walker BR, Soderberg S, Livingstone DE, Eliasson M, Johnson O, Andrew R, Olsson T (2002) Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11β-hydroxysteroid dehydrogenase type 1 activity. J Clin Endocrinol Metab 87:3330–3336PubMedGoogle Scholar
  65. 65.
    Westerbacka J, Yki-Jarvinen H, Vehkavaara S, Hakkinen AM, Andrew R, Wake DJ, Seckl JR, Walker BR (2003) Body fat distribution and cortisol metabolism in healthy men: enhanced 5β-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver. J Clin Endocrinol Metab 88:4924–4931PubMedGoogle Scholar
  66. 66.
    Paulmyer-Lacroix O, Boullu S, Oliver C, Alessi MC, Grino M (2002) Expression of the mRNA coding for 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue from obese patients: an in situ hybridization study. J Clin Endocrinol Metab 87:2701–2705PubMedGoogle Scholar
  67. 67.
    Lindsay RS, Wake DJ, Nair S, Bunt J, Livingstone DE, Permana PA, Tataranni PA, Walker BR (2003) Subcutaneous adipose 11β-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 88:2738–2744PubMedGoogle Scholar
  68. 68.
    Wake DJ, Rask E, Livingstone DE, Soderberg S, Olsson T, Walker BR (2003) Local and systemic impact of transcriptional up-regulation of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity. J Clin Endocrinol Metab 88:3983–3988PubMedGoogle Scholar
  69. 69.
    Kannisto K, Pietilainen KH, Ehrenborg E, Rissanen A, Kaprio J, Hamsten A, Yki-Jarvinen H (2004) Overexpression of 11β-hydroxysteroid dehydrogenase-1 in adipose tissue is associated with acquired obesity and features of insulin resistance: studies in young adult monozygotic twins. J Clin Endocrinol Metab 89:4414–4421PubMedGoogle Scholar
  70. 70.
    Sandeep TC, Andrew R, Homer NZ, Andrews RC, Smith K, Walker BR (2005) Increased in vivo regeneration of cortisol in adipose tissue in human obesity and effects of the 11β-hydroxysteroid dehydrogenase type 1 inhibitor carbenoxolone. Diabetes 54:872–879PubMedGoogle Scholar
  71. 71.
    Michailidou Z, Jensen MD, Dumesic DA, Chapman KE, Seckl JR, Walker BR, Morton NM (2007) Omental fat 11β-hydroxysteroid dehydrogenase type 1, but not glucocorticoid receptor, is correlated with fat cell size independently of obesity. Obesity 15:1155–1163PubMedCrossRefGoogle Scholar
  72. 72.
    Cooper MS, Bujalska I, Rabbitt E, Walker EA, Bland R, Sheppard MC, Hewison M, Stewart PM (2001) Modulation of 11β-hydroxysteroid dehydrogenase isozymes by proinflammatory cytokines in osteoblasts: an autocrine switch from glucocorticoid inactivation to activation. J Bone Miner Res 16:1037–1044PubMedGoogle Scholar
  73. 73.
    Gingras MC, Margolin JF (2000) Differential expression of multiple unexpected genes during U937 cell and macrophage differentiation detected by suppressive subtractive hybridization. Exp Hematol 28:65–76PubMedGoogle Scholar
  74. 74.
    Yong PY, Thong KJ, Andrew R, Walker BR, Hillier SG (2000) Development-related increase in cortisol biosynthesis by human granulosa cells. J Clin Endocrinol Metab 85:4728–4733PubMedGoogle Scholar
  75. 75.
    Hundertmark S, Dill A, Buhler H, Stevens P, Looman K, Ragosch V, Seckl JR, Lipka C (2002) 11β-hydroxysteroid dehydrogenase type 1: a new regulator of fetal lung maturation. Horm Metab Res 34:537–544PubMedGoogle Scholar
  76. 76.
    Speirs HJ, Seckl JR, Brown RW (2004) Ontogeny of glucocorticoid receptor and 11β-hydroxysteroid dehydrogenase type-1 gene expression identifies potential critical periods of glucocorticoid susceptibility during development. J Endocrinol 181:105–116PubMedGoogle Scholar
  77. 77.
    Thompson A, Han VK, Yang K (2004) Differential expression of 11β-hydroxysteroid dehydrogenase types 1 and 2 mRNA and glucocorticoid receptor protein during mouse embryonic development. J Steroid Biochem Mol Biol 88:367–375PubMedGoogle Scholar
  78. 78.
    Low SC, Assaad SN, Rajan V, Chapman KE, Edwards CRW, Seckl JR (1993) Regulation of 11β-hydroxysteroid dehydrogenase by sex steroids in vivo: further evidence for the existence of a second dehydrogenase in rat kidney. J Endocrinol 139:27–35PubMedGoogle Scholar
  79. 79.
    Gomez-Sanchez EP, Ganjam V, Chen YJ, Liu Y, Zhou MY, Toroslu C, Romero DG, Hughson MD, de Rodriguez A, Gomez-Sanchez CE (2003) Regulation of 11β-hydroxysteroid dehydrogenase enzymes in the rat kidney by estradiol. Am J Physiol Endocrinol Metab 285:E272–279PubMedGoogle Scholar
  80. 80.
    Stulnig TM, Oppermann U, Steffensen KR, Schuster GU, Gustafsson JA (2002) Liver X receptors downregulate 11β-hydroxysteroid dehydrogenase type 1 expression and activity. Diabetes 51:2426–2433PubMedGoogle Scholar
  81. 81.
    Hermanowski-Vosatka A, Gerhold D, Mundt SS, Loving VA, Lu M, Chen Y, Elbrecht A, Wu M, Doebber T, Kelly L, Milot D, Guo Q, Wang PR, Ippolito M, Chao YS, Wright SD, Thieringer R (2000) PPARα agonists reduce 11β-hydroxysteroid dehydrogenase type 1 in the liver. Biochem Biophys Res Commun 279:330–336PubMedGoogle Scholar
  82. 82.
    Berger J, Tanen M, Elbrecht A, Hermanowski-Vosatka A, Moller DE, Wright SD, Thieringer R (2001) PPARγ ligands inhibit adipocyte 11β-hydroxysteroid dehydrogenase type 1 expression and activity. J Biol Chem 276:12629–12635PubMedGoogle Scholar
  83. 83.
    Voice MW, Seckl JR, Edwards CRW, Chapman KE (1996) 11β-hydroxysteroid dehydrogenase type 1 expression in 2S-FAZA hepatoma cells is hormonally regulated; a model system for the study of hepatic glucocorticoid metabolism. Biochem J 317:621–625PubMedGoogle Scholar
  84. 84.
    Hammami MM, Siiteri PK (1991) Regulation of 11β-hydroxysteroid dehydrogenase activity in human skin fibroblasts: enzymatic modulation of glucocorticoid action. J Clin Endocrinol Metab 73:326–334PubMedCrossRefGoogle Scholar
  85. 85.
    Bujalska IJ, Kumar S, Hewison M, Stewart PM (1999) Differentiation of adipose stromal cells: the roles of glucocorticoids and 11β-hydroxysteroid dehydrogenase. Endocrinology 140:3188–3196PubMedGoogle Scholar
  86. 86.
    Sun K, Myatt L (2003) Enhancement of glucocorticoid-induced 11beta-hydroxysteroid dehydrogenase type 1 expression by proinflammatory cytokines in cultured human amnion fibroblasts. Endocrinology 144:5568–5577PubMedGoogle Scholar
  87. 87.
    Rajan V, Edwards CRW, Seckl JR (1996) 11β-hydroxysteroid dehydrogenase in cultured hippocampal cells reactivates inert 11-dehydrocorticosterone, potentiating neurotoxicity. J Neurosci 16:65–70PubMedGoogle Scholar
  88. 88.
    Low SC, Moisan M-P, Noble JM, Edwards CRW, Seckl JR (1994) Glucocorticoids regulate hippocampal 11β-hydroxysteroid dehydrogenase activity and gene expression in vivo in the rat. J Neuroendocrinol 6:285–290PubMedGoogle Scholar
  89. 89.
    Jamieson PM, Chapman KE, Seckl JR (1999) Tissue- and temporal-specific regulation of 11β-hydroxysteroid dehydrogenase type 1 by glucocorticoids in vivo. J Steroid Biochem Mol Biol 68:245–250PubMedGoogle Scholar
  90. 90.
    Jamieson PM, Fuchs E, Seckl JR (1997) Chronic psycho-social stress attenuates 11ß-hydroxysteroid dehydrogenase activity in the hippocampus and liver in the tree-shrew. Stress 2:123–132PubMedGoogle Scholar
  91. 91.
    Freeman L, Hewison M, Hughes SV, Evans KN, Hardie D, Means TK, Chakraverty R (2005) Expression of 11β-hydroxysteroid dehydrogenase type 1 permits regulation of glucocorticoid bioavailability by human dendritic cells. Blood 106:2042–2049PubMedGoogle Scholar
  92. 92.
    Vagnerova K, Kverka M, Klusonova P, Ergang P, Miksik I, Tlaskalova-Hogenova H, Pacha J (2006) Intestinal inflammation modulates expression of 11β-hydroxysteroid dehydrogenase in murine gut. J Endocrinol 191:497–503PubMedGoogle Scholar
  93. 93.
    Escher G, Galli I, Vishwanath BS, Frey BM, Frey FJ (1997) Tumor necrosis factor α and interleukin 1β enhance the cortisone/cortisol shuttle. J Exp Med 186:189–198PubMedGoogle Scholar
  94. 94.
    Tomlinson JW, Moore J, Cooper MS, Bujalska I, Shahmanesh M, Burt C, Strain A, Hewison M, Stewart PM (2001) Regulation of expression of 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines. Endocrinology 142:1982–1989PubMedGoogle Scholar
  95. 95.
    Charriere G, Cousin B, Arnaud E, Andre M, Bacou F, Penicaud L, Casteilla L (2003) Preadipocyte conversion to macrophage. Evidence of plasticity. J Biol Chem 278:9850–9855PubMedGoogle Scholar
  96. 96.
    Tetsuka M, Thomas FJ, Thomas MJ, Anderson RA, Mason JI, Hillier SG (1997) Differential expression of messenger ribonucleic acids encoding 11β-hydroxysteroid dehydrogenase types 1 and 2 in human granulosa cells. J Clin Endocrinol Metab 82:2006–2009PubMedGoogle Scholar
  97. 97.
    Tetsuka M, Milne M, Simpson GE, Hillier SG (1999) Expression of 11β-hydroxysteroid dehydrogenase, glucocorticoid receptor, and mineralocorticoid receptor genes in rat ovary. Biol Reprod 60:330–335PubMedGoogle Scholar
  98. 98.
    Yong PY, Harlow C, Thong KJ, Hillier SG (2002) Regulation of 11β-hydroxysteroid dehydrogenase type 1 gene expression in human ovarian surface epithelial cells by interleukin-1. Hum Reprod 17:2300–2306PubMedGoogle Scholar
  99. 99.
    Hardy RS, Filer A, Cooper MS, Parsonage G, Raza K, Hardie DL, Rabbitt EH, Stewart PM, Buckley CD, Hewison M (2006) Differential expression, function and response to inflammatory stimuli of 11β-hydroxysteroid dehydrogenase type 1 in human fibroblasts: a mechanism for tissue-specific regulation of inflammation. Arthritis Res Ther 8:R108PubMedGoogle Scholar
  100. 100.
    Alfaidy N, Xiong ZG, Myatt L, Lye SJ, MacDonald JF, Challis JR (2001) Prostaglandin F2α potentiates cortisol production by stimulating 11β-hydroxysteroid dehydrogenase 1: a novel feedback loop that may contribute to human labor. J Clin Endocrinol Metab 86:5585–5592PubMedGoogle Scholar
  101. 101.
    Cai T, Wong B, Mundt SS, Thieringer R, Wright SD, Hermanowski-Vosatka A (2001) Induction of 11β-hydroxysteroid dehydrogenase type 1 but not -2 in human aortic smooth muscle cells by inflammatory stimuli. J Steroid Biochem Mol Biol 77:117–122PubMedGoogle Scholar
  102. 102.
    Heiniger CD, Rochat MK, Frey FJ, Frey BM (2001) TNF-alpha enhances intracellular glucocorticoid availability. FEBS Lett 507:351–356PubMedGoogle Scholar
  103. 103.
    Moisan M-P, Edwards CRW, Seckl JR (1992) Differential promoter usage by the rat 11β-hydroxysteroid dehydrogenase gene. Mol Endocrinol 6:1082–1087PubMedGoogle Scholar
  104. 104.
    Bruley C, Lyons V, Worsley AG, Wilde MD, Darlington GD, Morton NM, Seckl JR, Chapman KE (2006) A novel promoter for the 11β-hydroxysteroid dehydrogenase type 1 gene is active in lung and is C/EBPα independent. Endocrinology 147:2879–2885PubMedGoogle Scholar
  105. 105.
    Mercer W, Obeyesekere V, Smith R, Krozowski Z (1993) Characterization of 11β-HSD1B gene expression and enzymatic activity. Mol Cell Endocrinol 92:247–251PubMedGoogle Scholar
  106. 106.
    Williams LJS, Lyons V, MacLeod I, Rajan V, Darlington GJ, Poli V, Seckl JR, Chapman KE (2000) C/EBP regulates hepatic transcription of 11β-hydroxysteroid dehydrogenase type 1; a novel mechanism for cross talk between the C/EBP and glucocorticoid signalling pathways. J Biol Chem 275:30232–30239PubMedGoogle Scholar
  107. 107.
    McKnight SL, Lane MD, Gluecksohn-Waelsch S (1989) Is CCAAT/enhancer-binding protein a central regulator of energy metabolism? Genes Dev 3:2021–2024PubMedGoogle Scholar
  108. 108.
    Darlington GJ, Wang N, Hanson RW (1995) C/EBPα: a critical regulator of genes governing integrative metabolic processes. Curr Opin Genet Dev 5:565–570PubMedGoogle Scholar
  109. 109.
    Sieweke MH, Graf T (1998) A transcription factor party during blood cell differentiation. Curr Opin Genet Dev 8:545–551PubMedGoogle Scholar
  110. 110.
    Iwasaki H, Mizuno S, Arinobu Y, Ozawa H, Mori Y, Shigematsu H, Takatsu K, Tenen DG, Akashi K (2006) The order of expression of transcription factors directs hierarchical specification of hematopoietic lineages. Genes Dev 20:3010–3021PubMedGoogle Scholar
  111. 111.
    Kotelevtsev Y, Holmes MC, Burchell A, Houston PM, Schmoll D, Jamieson P, Best R, Brown R, Edwards CRW, Seckl JR, Mullins JJ (1997) 11β-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid inducible responses and resist hyperglycaemia on obesity or stress. Proc Natl Acad Sci USA 94:14924–14929PubMedGoogle Scholar
  112. 112.
    Kellendonk C, Eiden S, Kretz O, Schutz G, Schmidt I, Tronche F, Simon E (2002) Inactivation of the GR in the nervous system affects energy accumulation. Endocrinology 143:2333–2340PubMedGoogle Scholar
  113. 113.
    Morton NM, Paterson JM, Masuzaki H, Holmes MC, Staels B, Fievet C, Walker BR, Flier JS, Mullins JJ, Seckl JR (2004) Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11β-hydroxysteroid dehydrogenase type 1-deficient mice. Diabetes 53:931–938PubMedGoogle Scholar
  114. 114.
    Morton NM, Holmes MC, Fiévet C, Staels B, Tailleux A, Mullins JJ, Seckl JR (2001) Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11β-hydroxysteroid dehydrogenase type 1 null mice. J Biol Chem 276:41293–41300PubMedGoogle Scholar
  115. 115.
    Masuzaki H, Paterson J, Shinyama H, Morton NM, Mullins JJ, Seckl JR, Flier JS (2001) A transgenic model of visceral obesity and the metabolic syndrome. Science 294:2166–2170PubMedGoogle Scholar
  116. 116.
    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 112:83–90PubMedGoogle Scholar
  117. 117.
    Kershaw EE, Morton NM, Dhillon H, Ramage L, Seckl JR, Flier JS (2005) Adipocyte-specific glucocorticoid inactivation protects against diet-induced obesity. Diabetes 54:1023–1031PubMedGoogle Scholar
  118. 118.
    Paterson JM, Morton NM, Fiévet C, Kenyon CJ, Holmes MC, Staels B, Seckl JR, Mullins JJ (2004) Metabolic syndrome without obesity: hepatic overexpression of 11β-hydroxysteroid dehydrogenase type 1 in transgenic mice. Proc Natl Acad Sci USA 101:7088–7093PubMedGoogle Scholar
  119. 119.
    Thieringer R, Hermanowski-Vosatka A (2005) Inhibition of 11β-HSD1 as a novel treatment for the metabolic syndrome: do glucocorticoids play a role? Expert Rev Cardiovasc Ther 3:911–924PubMedGoogle Scholar
  120. 120.
    Masuzaki H, Flier JS (2003) Tissue-specific glucocorticoid reactivating enzyme, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) – a promising drug target for the treatment of metabolic syndrome. Curr Drug Targets Immune Endocr Metabol Disord 3:255–262PubMedGoogle Scholar
  121. 121.
    Alberts P, Engblom L, Edling N, Forsgren M, Klingstrom G, Larsson C, Ronquist-Nii Y, Ohman B, Abrahmsen L (2002) Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 decreases blood glucose concentrations in hyperglycaemic mice. Diabetologia 45:1528–1532PubMedGoogle Scholar
  122. 122.
    Alberts P, Nilsson C, Selen G, Engblom LO, Edling NH, Norling S, Klingstrom G, Larsson C, Forsgren M, Ashkzari M, Nilsson CE, Fiedler M, Bergqvist E, Ohman B, Bjorkstrand E, Abrahmsen LB (2003) Selective inhibition of 11β-hydroxysteroid dehydrogenase type 1 improves hepatic insulin sensitivity in hyperglycemic mice strains. Endocrinology 144:4755–4762PubMedGoogle Scholar
  123. 123.
    Hermanowski-Vosatka A, Balkovec JM, Cheng K, Chen HY, Hernandez M, Koo GC, Le Grand CB, Li Z, Metzger JM, Mundt SS, Noonan H, Nunes CN, Olson SH, Pikounis B, Ren N, Robertson N, Schaeffer JM, Shah K, Springer MS, Strack AM, Strowski M, Wu K, Wu T, Xiao J, Zhang BB, Wright SD, Thieringer R (2005) 11β-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice. J Exp Med 202:517–527PubMedGoogle Scholar
  124. 124.
    Wang SJ, Birtles S, de Schoolmeester J, Swales J, Moody G, Hislop D, O’Dowd J, Smith DM, Turnbull AV, Arch JR (2006) Inhibition of 11β-hydroxysteroid dehydrogenase type 1 reduces food intake and weight gain but maintains energy expenditure in diet-induced obese mice. Diabetologia 49:1333–1337PubMedGoogle Scholar
  125. 125.
    Yeager MP, Guyre PM, Munck AU (2004) Glucocorticoid regulation of the inflammatory response to injury. Acta Anaesthesiol Scand 48:799–813PubMedGoogle Scholar
  126. 126.
    Smoak KA, Cidlowski JA (2004) Mechanisms of glucocorticoid receptor signaling during inflammation. Mech Ageing Dev 125:697–706PubMedGoogle Scholar
  127. 127.
    Ashwell JD, Lu FW, Vacchio MS (2000) Glucocorticoids in T cell development and function. Ann Rev Immunol 18:309–345Google Scholar
  128. 128.
    Sternberg EM (2001) Neuroendocrine regulation of autoimmune/inflammatory disease. J Endocrinol 169:429–435PubMedGoogle Scholar
  129. 129.
    Munck A, Naray-Fejes-Toth A (1992) The ups and downs of glucocorticoid physiology. Permissive and suppressive effects revisited. Mol Cell Endocrinol 90:C1–C4PubMedGoogle Scholar
  130. 130.
    Sapolsky RM, Romero LM, Munck AU (2000) How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev 21:55–89PubMedGoogle Scholar
  131. 131.
    Barnes PJ (1998) Anti-inflammatory actions of glucocorticoids: molecular mechanisms. Clin Sci (Lond) 94:557–572Google Scholar
  132. 132.
    Liu YQ, Cousin JM, Hughes J, VanDamme J, Seckl JR, Haslett C, Dransfield I, Savill J, Rossi AG (1999) Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes. J Immunol 162:3639–3646PubMedGoogle Scholar
  133. 133.
    Munck A, Guyre PM, Holbrook NJ (1984) Physiological functions of glucocorticoids in stress and their relationship to pharmacological actions. Endocrinol Rev 5:25–44Google Scholar
  134. 134.
    Baumann H, Gauldie J (1994) The acute phase response. Immunol Today 15:74–80PubMedGoogle Scholar
  135. 135.
    Chapman KE, Gilmour JS, Coutinho AE, Savill JS, Seckl JR (2006) 11β-hydroxysteroid dehydrogenase type 1 – a role in inflammation? Mol Cell Endocrinol 248:3–8PubMedGoogle Scholar
  136. 136.
    Botto M, Dell’Agnola C, Bygrave AE, Thompson EM, Cook HT, Petry F, Loos M, Pandolfi PP, Walport MJ (1998) Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies. Nat Genet 19:56–59PubMedGoogle Scholar
  137. 137.
    Taylor PR, Carugati A, Fadok VA, Cook HT, Andrews M, Carroll MC, Savill JS, Henson PM, Botto M, Walport MJ (2000) A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J Exp Med 192:359–366PubMedGoogle Scholar
  138. 138.
    Coutinho AE, Gray M, Sawatzky DA, Brownstein D, Gilmour JS, Mullins J, Seckl JR, Savill JS, Chapman KE (2006) Deficiency in 11β-hydroxysteroid dehydrogenase type 1 results in a more rapid and severe inflammation. In: Abstracts of the 88th meeting of the American Endocrine Society P2-108Google Scholar
  139. 139.
    Schmidt M, Weidler C, Naumann H, Anders S, Scholmerich J, Straub RH (2005) Reduced capacity for the reactivation of glucocorticoids in rheumatoid arthritis synovial cells: possible role of the sympathetic nervous system? Arthritis Rheum 52:1711–1720PubMedGoogle Scholar
  140. 140.
    Ross R (1999) Atherosclerosis – an inflammatory disease. N Engl J Med 340:115–126PubMedGoogle Scholar
  141. 141.
    Wei L, MacDonald TM, Walker BR (2004) Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 141:764–770PubMedGoogle Scholar
  142. 142.
    Souverein PC, Berard A, Van Staa TP, Cooper C, Egberts ACG, Leufkens HGM, Walker BR (2004) Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart 90:859–865PubMedGoogle Scholar
  143. 143.
    Roland BL, Li KXZ, Funder JW (1995) Hybridization histochemical localization of 11β-hydroxysteroid dehydrogenase type 2 in rat brain. Endocrinology 136:4697–4700PubMedGoogle Scholar
  144. 144.
    Robson AC, Leckie CM, Seckl JR, Holmes MC (1998) 11β-hydroxysteroid dehydrogenase type 2 in the postnatal and adult rat brain. Mol Brain Res 61:1–10PubMedGoogle Scholar
  145. 145.
    Sandeep TC, Yau JL, MacLullich AM, Noble J, Deary IJ, Walker BR, Seckl JR (2004) 11β-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. Proc Natl Acad Sci USA 101:6734–6739PubMedGoogle Scholar
  146. 146.
    McEwen BS, de Kloet ER, Rostene W (1986) Adrenal steroid receptors and action in the nervous system. Physiol Rev 66:1121–1188PubMedGoogle Scholar
  147. 147.
    DeKloet ER, Vreugdenhil E, Oitzl MS, Joels M (1998) Brain corticosteroid receptor balance in health and disease. Endocrine Rev 19:269–301Google Scholar
  148. 148.
    Sapolsky RM (2000) Glucocorticoids and hippocampal atrophy in neuropsychiatric disorders. Arch Gen Psychiatr 57:925–935PubMedGoogle Scholar
  149. 149.
    Sapolsky RM, Pulsinelli WA (1985) Glucocorticoids potentiate ischemic injury to neurons: therapeutic implications. Science 229:1397–1400PubMedGoogle Scholar
  150. 150.
    Sapolsky RM (1985) A mechanism for glucocorticoid toxicity in the hippocampus: increased neuronal vulnerability to metabolic insults. J Neurosci 5:1228–1232PubMedGoogle Scholar
  151. 151.
    Gould E, Tanapat P (1999) Stress and hippocampal neurogenesis. Biol Psychiatr 46:1472–1479Google Scholar
  152. 152.
    Lee AL, Ogle WO, Sapolsky RM (2002) Stress and depression: possible links to neuron death in the hippocampus. Bipolar Disord 4:117–128PubMedGoogle Scholar
  153. 153.
    Grillon C, Smith K, Haynos A, Nieman LK (2004) Deficits in hippocampus-mediated Pavlovian conditioning in endogenous hypercortisolism. Biol Psychiatr 56:837–843Google Scholar
  154. 154.
    Starkman MN, Gebarski SS, Berent S, Schteingart DE (1992) Hippocampal formation volume, memory dysfunction and cortisol levels in patients with Cushing’s syndrome. Biol Psychiatr 32:756–765Google Scholar
  155. 155.
    Woolley CS, Gould E, McEwen BS (1990) Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:225–231PubMedGoogle Scholar
  156. 156.
    Sapolsky RM, Uno H, Rebert CS, Finch CE (1990) Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci 10:2897–2902PubMedGoogle Scholar
  157. 157.
    Meaney MJ, O’Donnell D, Rowe W, Tannenbaum B, Steverman A, Walker M, Nair NPV, Lupien S (1995) Individual differences in hypothalamic–pituitary–adrenal activity in later life and hippocampal aging. Exp Gerontol 30:229–251PubMedGoogle Scholar
  158. 158.
    Green KN, Billings LM, Roozendaal B, McGaugh JL, LaFerla FM (2006) Glucocorticoids increase amyloid-beta and tau pathology in a mouse model of Alzheimer’s disease. J Neurosci 26:9047–9056PubMedGoogle Scholar
  159. 159.
    Issa AM, Rowe W, Gauthier S, Meaney MJ (1990) Hypothalamic–pituitary–adrenal activity in aged, cognitively impaired and cognitively unimpaired rats. J Neurosci 10:3247–3254PubMedGoogle Scholar
  160. 160.
    Landfield PW, Waymire JC, Lynch G (1978) Hippocampal aging and adrenocorticoids: quantitative correlations. Science 202:1098–1102PubMedGoogle Scholar
  161. 161.
    Harris HJ, Kotelevtsev Y, Mullins JJ, Seckl JR, Holmes MC (2001) Intracellular regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase (11β-HSD)-1 plays a key role in regulation of the hypothalamic-pituitary-adrenal axis: analysis of 11β-HSD-1 deficient mice. Endocrinology 142:114–120PubMedGoogle Scholar
  162. 162.
    Carter RN, Tworowska U, Seckl JR, Holmes MC (2006) 11β-hydroxysteroid dehydrogenase modulation of HPA function – importance of genetic background. In: Abstracts of the 8th European congress of endocrinology OC39Google Scholar
  163. 163.
    Johnstone HA, Wigger A, Douglas AJ, Neumann ID, Landgraf R, Seckl JR, Russell JA (2000) Attenuation of hypothalamic–pituitary–adrenal axis stress responses in late pregnancy: changes in feedforward and feedback mechanisms. J Neuroendocrinol 12:811–822PubMedGoogle Scholar
  164. 164.
    Paterson JM, Holmes MC, Kenyon CJ, Carter R, Mullins JJ, Seckl JR (2007) Liver-selective transgene rescue of hypothalamic–pituitary–adrenal axis dysfunction in 11β-hydroxysteroid dehydrogenase type 1 deficient mice. Endocrinology 148:961–966 PubMedGoogle Scholar
  165. 165.
    la Fleur SE, Manalo SL, Roy M, Houshyar H, Dallman MF (2005) Hepatic vagotomy alters limbic and hypothalamic neuropeptide responses to insulin-dependent diabetes and voluntary lard ingestion. Eur J Neurosci 21:2733–2742PubMedGoogle Scholar
  166. 166.
    Ajilore OA, Sapolsky RM (1999) In vivo characterization of 11β-hydroxysteroid dehydrogenase in rat hippocampus using glucocorticoid neuroendangerment as an endpoint. Neuroendocrinology 69:138–144PubMedGoogle Scholar
  167. 167.
    Yau JL, Noble J, Kenyon CJ, Hibberd C, Kotelevtsev Y, Mullins JJ, Seckl JR (2001) Lack of tissue glucocorticoid reactivation in 11β-hydroxysteroid dehydrogenase type 1 knockout mice ameliorates age-related learning impairments. Proc Natl Acad Sci USA 98:4716–4721PubMedGoogle Scholar
  168. 168.
    Yau JLW, Olsson T, Morris RGM, Meaney MJ, Seckl JR (1995) Glucocorticoids, hippocampal corticosteroid receptor gene expression and antidepressant treatment: relationship with spatial learning in young and aged rats. Neuroscience 66:571–581PubMedGoogle Scholar
  169. 169.
    Walker BR, Connacher AA, Lindsay RM, Webb DJ, Edwards CRW (1995) Carbenoxolone increases hepatic insulin sensitivity in man: a novel role for 11-oxosteroid reductase in enhancing glucocorticoid receptor activation. J Clin Endocrinol Metab 80:3155–3159PubMedGoogle Scholar
  170. 170.
    Andrews RC, Rooyackers O, Walker BR (2003) Effects of the 11β-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab 88:285–291PubMedGoogle Scholar
  171. 171.
    de Quervain DJ, Poirier R, Wollmer MA, Grimaldi LM, Tsolaki M, Streffer JR, Hock C, Nitsch RM, Mohajeri MH, Papassotiropoulos A (2004) Glucocorticoid-related genetic susceptibility for Alzheimer’s disease. Hum Mol Genet 13:47–52PubMedGoogle Scholar
  172. 172.
    Deary IJ, Hayward C, Permana PA, Nair S, Whalley LJ, Starr JM, Chapman KE, Walker BR, Seckl JR (2006) Polymorphisms in the gene encoding 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) and lifetime cognitive change. Neurosci Lett 393:74–77PubMedGoogle Scholar
  173. 173.
    Visser M, Pahor M, Taaffe DR, Goodpaster BH, Simonsick EM, Newman AB, Nevitt M, Harris TB (2002) Relationship of interleukin-6 and tumor necrosis factor-alpha with muscle mass and muscle strength in elderly men and women: the Health ABC Study. J Gerontol A Biol Sci Med Sci 57:M326–332PubMedGoogle Scholar
  174. 174.
    Bruunsgaard H, Skinhoj P, Pedersen AN, Schroll M, Pedersen BK (2000) Ageing, tumour necrosis factor-alpha (TNF-alpha) and atherosclerosis. Clin Exp Immunol 121:255–260PubMedGoogle Scholar
  175. 175.
    Bruunsgaard H, Andersen-Ranberg K, Hjelmborg JB, Pedersen BK, Jeune B (2003) Elevated levels of tumor necrosis factor alpha and mortality in centenarians. Am J Med 115:278–283PubMedGoogle Scholar
  176. 176.
    Yaffe K, Lindquist K, Penninx BW, Simonsick EM, Pahor M, Kritchevsky S, Launer L, Kuller L, Rubin S, Harris T (2003) Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 61:76–80PubMedGoogle Scholar
  177. 177.
    Kumari M, Grahame-Clarke C, Shanks N, Marmot M, Lightman S, Vallance P (2003) Chronic stress accelerates atherosclerosis in the apolipoprotein E deficient mouse. Stress 6:297–299PubMedCrossRefGoogle Scholar
  178. 178.
    Stewart R (1998) Cardiovascular factors in Alzheimer’s disease. J Neurol Neurosurg Psychiatr 65:143–147PubMedCrossRefGoogle Scholar
  179. 179.
    Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430:631PubMedGoogle Scholar
  180. 180.
    Kizaki T, Ookawara T, Oh-Ishi S, Itoh Y, Iwabuchi K, Onoe K, Day NK, Good RA, Ohno H (1998) An increase in basal glucocorticoid concentration with age induces suppressor macrophages with high-density Fc gamma RII/III. Immunology 93:409–414PubMedGoogle Scholar
  181. 181.
    Lupien S, Lecours AR, Lussier I, Schwartz G, Nair NP, Meaney MJ (1994) Basal cortisol levels and cognitive deficits in human aging. J Neurosci 14:2893–2903PubMedGoogle Scholar
  182. 182.
    Tannenbaum BM, Brindley DN, Tannenbaum GS, Dallman MF, McArthur MD, Meaney MJ (1997) High-fat feeding alters both basal and stress-induced hypothalamic–pituitary–adrenal activity in the rat. Am J Physiol 273:E1168–E1177PubMedGoogle Scholar
  183. 183.
    Björntorp P, Rosmond R (2000) Obesity and cortisol. Nutrition 16:924–936PubMedGoogle Scholar
  184. 184.
    Sartipy P, Loskutoff DJ (2003) Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 100:7265–7270PubMedGoogle Scholar
  185. 185.
    Faggiano A, Pivonello R, Spiezia S, De Martino MC, Filippella M, Di Somma C, Lombardi G, Colao A (2003) Cardiovascular risk factors and common carotid artery caliber and stiffness in patients with Cushing’s disease during active disease and 1 year after disease remission. J Clin Endocrinol Metab 88:2527–2533PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Endocrinology Unit, Centre for Cardiovascular Sciences, Queen’s Medical Research InstituteUniversity of EdinburghEdinburghUK

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