Horm Metab Res 2002; 34(11/12): 746-751
DOI: 10.1055/s-2002-38242
Review
© Georg Thieme Verlag Stuttgart · New York

The Functional Consequences of 11β-Hydroxysteroid Dehydrogenase Expression in Adipose Tissue

J.  W.  Tomlinson1 , P.  M.  Stewart1
  • 1Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK
Further Information

Publication History

Received 1 October 2002

Accepted after revision 6 November 2002

Publication Date:
27 March 2003 (online)

Abstract

Clinical observations have highlighted the link between glucocorticoids and obesity. While exogenous glucocorticoids in excess predispose to the development of central obesity, we have focused on cortisol metabolism within human adipose tissue. 11β-hydroxysteroid dehydrogenase (11β-HSD) inter-converts the active glucocorticoid, cortisol, and inactive cortisone. 11β-HSD1, the only isoform expressed in adipose tissue, acts predominantly as an oxoreductase to generate cortisol. Expression is higher in omental compared to subcutaneous preadipocytes and activity and expression are potently regulated by growth factors and cytokines. Mice over-expressing 11β-HSD1 specifically within adipocytes develop central obesity. However, the situation is less clear in humans. Globally, there appears to be inhibition of the enzyme, but expression in human obesity is still not fully characterized; its functional role in adipocyte biology remains to be elucidated. In vitro, 11β-HSD1 appears to function in promoting adipocyte differentiation and limiting preadipocyte proliferation, but the impact of these effects in vivo upon the regulation of fat mass remains to be defined. Clinical studies utilizing selective 11β-HSD1 inhibitors may help to answer this question.

References

  • 1 Fraser R, Ingram M C, Anderson N H, Morrison C, Davies E, Connell J M. Cortisol effects on body mass, blood pressure, and cholesterol in the general population.  Hypertension. 1999;  33 (6) 1364-1368
  • 2 Dunkleman S S, Fairhurst B, Plager J, Waterhouse C. Cortisol metabolism in obesity.  J Clin Endocrinol Metab. 1964;  24 832-841
  • 3 Marin P, Darin N, Amemiya T, Andersson B, Jern S, Bjorntorp P. Cortisol secretion in relation to body fat distribution in obese premenopausal women.  Metabolism. 1992;  41 (8) 882-886
  • 4 Duclos M, Corcuff J B, Etcheverry N, Rashedi M, Tabarin A, Roger P. Abdominal obesity increases overnight cortisol excretion.  J Endocrinol Invest. 1999;  22 (6) 465-471
  • 5 Rosmond R, Dallman M F, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and hemodynamic abnormalities.  J Clin Endocrinol Metab. 1998;  83 (6) 1853-1859
  • 6 Gregoire F M, Smas C M, Sul H S. Understanding adipocyte differentiation.  Physiol Rev. 1998;  78 (3) 783-809
  • 7 Kras K M, Hausman D B, Hausman G J, Martin R J. Adipocyte development is dependent upon stem cell recruitment and proliferation of preadipocytes.  Obes Res. 1999;  7 (5) 491-497
  • 8 Lakshmi V, Monder C. Purification and characterization of the corticosteroid 11 beta-dehydrogenase component of the rat liver 11 beta-hydroxysteroid dehydrogenase complex.  Endocrinology. 1988;  123 (5) 2390-2398
  • 9 Jamieson P M, Walker B R, Chapman K E, Andrew R, Rossiter S, Seckl J R. 11 beta-hydroxysteroid dehydrogenase type 1 is a predominant 11 beta- reductase in the intact perfused rat liver.  J Endocrinol. 2000;  165(3) 685-692
  • 10 Agarwal A K, Tusie-Luna M T, Monder C, White P C. Expression of 11 beta-hydroxysteroid dehydrogenase using recombinant vaccinia virus.  Mol Endocrinol. 1990;  4 (12) 1827-1832
  • 11 Ricketts M L, Verhaeg J M, Bujalska I, Howie A J, Rainey W E, Stewart P M. Immunohistochemical localization of type 1 11beta-hydroxysteroid dehydrogenase in human tissues.  J Clin Endocrinol Metab. 1998;  83 (4) 1325-1335
  • 12 Cooper M S, Walker E A, Bland R, Fraser W D, Hewison M, Stewart P M. Expression and functional consequences of 11beta-hydroxysteroid dehydrogenase activity in human bone.  Bone. 2000;  27 (3) 375-381
  • 13 Rauz S, Walker E A, Shackleton C H, Hewison M, Murray P I, Stewart P M. Expression and putative role of 11 beta-hydroxysteroid dehydrogenase isozymes within the human eye.  Invest Ophthalmol Vis Sci. 2001;  42 (9) 2037-2042
  • 14 Rodin A, Thakkar H, Taylor N, Clayton R. Hyperandrogenism in polycystic ovary syndrome. Evidence of dysregulation of 11 beta-hydroxysteroid dehydrogenase [see comments].  N Engl J Med. 1994;  330 (7) 460-465
  • 15 Cooper M S, Rabbitt E H, Goddard P E, Bartlett W A, Hewison M, Stewart P M. Osteoblastic 11beta-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure.  J Bone Miner Res. 2002;  17 (6) 979-986
  • 16 Stewart P M, Krozowski Z S, Gupta A. et al . Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11 beta-hydroxysteroid dehydrogenase type 2 gene.  Lancet. 1996;  347 (8994) 88-91
  • 17 Bujalska I J, Kumar S, Stewart P M. Does central obesity reflect “Cushing’s disease of the omentum”?.  Lancet. 1997;  349 (9060) 1210-1213
  • 18 Paulmyer-Lacroix O, Boullu S, Oliver C, Alessi M C, Grino M. 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. 2002;  87 (6) 2701-2705
  • 19 Tomlinson J W, Sinha B, Bujalska I, Hewison M, Stewart P M. Expression of 11 beta-hydroxysteroid dehydrogenase type 1 in adipose tissue is not increased in human obesity.  J Clin Endocrinol Metab. 2002;  87 (in press)
  • 20 Moore J S, Monson J P, Kaltsas G. et al . Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies.  J Clin Endocrinol Metab. 1999;  84 (11) 4172-4177
  • 21 Tomlinson J W, Moore J, Cooper M S. et al . Regulation of expression of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue: tissue-specific induction by cytokines.  Endocrinology. 2001;  142 (5) 1982-1989
  • 22 Berger J, Tanen M, Elbrecht A. et al . Peroxisome proliferator-activated receptor-gamma ligands inhibit adipocyte 11beta-hydroxysteroid dehydrogenase type 1 expression and activity.  J Biol Chem. 2001;  276 (16) 12 629-12 635
  • 23 Miller K K, Daly P A, Sentochnik D. et al . Pseudo-Cushing’s syndrome in human immunodeficiency virus-infected patients.  Clin Infect Dis. 1998;  27 (1) 68-72
  • 24 Mori Y, Murakawa Y, Okada K. et al . Effect of troglitazone on body fat distribution in type 2 diabetic patients.  Diabetes Care. 1999;  22 (6) 908-912
  • 25 Kawai T, Takei I, Oguma Y. et al . Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes.  Metabolism. 1999;  48 (9) 1102-1107
  • 26 Akazawa S, Sun F, Ito M, Kawasaki E, Eguchi K. Efficacy of troglitazone on body fat distribution in type 2 diabetes.  Diabetes Care. 2000;  23 (8) 1067-1071
  • 27 Hauner H, Schmid P, Pfeiffer E F. Glucocorticoids and insulin promote the differentiation of human adipocyte precursor cells into fat cells.  J Clin Endocrinol Metab. 1987;  64 (4) 832-835
  • 28 Hauner H, Wabitsch M, Pfeiffer E F. Differentiation of adipocyte precursor cells from obese and nonobese adult women and from different adipose tissue sites.  Horm Metab Res. 1988;  19 (Suppl.) 35-39
  • 29 Auboeuf D, Rieusset J, Fajas L. et al . Tissue distribution and quantification of the expression of mRNAs of peroxisome proliferator-activated receptors and liver X receptor-alpha in humans: no alteration in adipose tissue of obese and NIDDM patients.  Diabetes. 1997;  46 (8) 1319-1327
  • 30 Vidal-Puig A J, Considine R V, Jimenez-Linan M. et al . Peroxisome proliferator-activated receptor gene expression in human tissues. Effects of obesity, weight loss, and regulation by insulin and glucocorticoids.  J Clin Invest. 1997;  99 (10) 2416-2422
  • 31 Bujalska I J, Kumar S, Hewison M, Stewart P M. Differentiation of adipose stromal cells: the roles of glucocorticoids and 11beta-hydroxysteroid dehydrogenase.  Endocrinology. 1999;  140 (7) 3188-3196
  • 32 Bujalska I J, Walker E A, Hewison M, Stewart P M. A switch in dehydrogenase to reductase activity of 11 beta- hydroxysteroid dehydrogenase type 1 upon differentiation of human omental adipose stromal cells.  J Clin Endocrinol Metab. 2002;  87 (3) 1205-1210
  • 33 Sanchez I, Goya L, Vallerga A K, Firestone G L. Glucocorticoids reversibly arrest rat hepatoma cell growth by inducing an early G1 block in cell cycle progression.  Cell Growth Differ. 1993;  4 (3) 215-225
  • 34 Rogatsky I, Trowbridge J M, Garabedian M J. Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms.  Mol Cell Biol. 1997;  17 (6) 3181-3193
  • 35 Rabbitt E H, Lavery G G, Walker E A, Cooper M S, Stewart P M, Hewison M. Prereceptor regulation of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase: a novel determinant of cell proliferation.  FASEB J. 2002;  16 (1) 36-44
  • 36 Gregoire F, Genart C, Hauser N, Remacle C. Glucocorticoids induce a drastic inhibition of proliferation and stimulate differentiation of adult rat fat cell precursors.  Exp Cell Res. 1991;  196 (2) 270-278
  • 37 Livingstone D E, Jones G C, Smith K. et al . Understanding the role of glucocorticoids in obesity: tissue-specific alterations of corticosterone metabolism in obese Zucker rats.  Endocrinology. 2000;  141 (2) 560-563
  • 38 Kotelevtsev Y, Holmes M C, Burchell A. et al . 11beta-hydroxysteroid dehydrogenase type 1 knockout mice show attenuated glucocorticoid-inducible responses and resist hyperglycemia on obesity or stress.  Proc Natl Acad Sci U S A. 1997;  94 (26) 14 924-14 929
  • 39 Morton N M, Patterson J M, Holmes M C, Walker B R, Mullins J J, Seckl J R. 11 beta-hydroxysteroid dehydrogeanse type 1 null mice resist dietary obesity and its metabolic consequences. Proceedings of the 84th annual meeting of the.  Endocrine Society. 2002;  OR17-3 (abstract)
  • 40 Morton N M, Holmes M C, Fievet C. et al . Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice.  J Biol Chem. 2001;  276 (44) 41 293-41 300
  • 41 Masuzaki H, Paterson J, Shinyama H. et al . A transgenic model of visceral obesity and the metabolic syndrome.  Science. 2001;  294 (5549) 2166-2170
  • 42 Palermo M, Shackleton C H, Mantero F, Stewart P M. Urinary free cortisone and the assessment of 11 beta-hydroxysteroid dehydrogenase activity in man.  Clin Endocrinol (Oxf). 1996;  45 (5) 605-611
  • 43 Stewart P M, Boulton A, Kumar S, Clark P M, Shackleton C H. Cortisol metabolism in human obesity: impaired cortisone → cortisol conversion in subjects with central adiposity.  Journal of Clinical Endocrinology & Metabolism. 1999;  84 (3) 1022-1027
  • 44 Rask E, Olsson T, Soderberg S. et al . Tissue-Specific Dysregulation of Cortisol Metabolism in Human Obesity.  J Clin Endocrinol Metab. 2001;  86 (3) 1418-1421
  • 45 Rask E, Walker B R, Soderberg S. et al . Tissue-specific changes in peripheral cortisol metabolism in obese women: increased adipose 11beta-hydroxysteroid dehydrogenase type 1 activity.  J Clin Endocrinol Metab. 2002;  87 (7) 3330-3336
  • 46 Katz J R, Mohamed-Ali V, Wood P J, Yudkin J S, Coppack S W. An in vivo study of the cortisol-cortisone shuttle in subcutaneous abdominal adipose tissue.  Clin Endocrinol (Oxf). 1999;  50 (1) 63-68
  • 47 Gelding S V, Taylor N F, Wood P J. et al . The effect of growth hormone replacement therapy on cortisol-cortisone interconversion in hypopituitary adults: evidence for growth hormone modulation of extrarenal 11 beta-hydroxysteroid dehydrogenase activity.  Clin Endocrinol (Oxf). 1998;  48 (2) 153-162
  • 48 Trainer P J, Drake W M, Perry L A, Taylor N F, Besser G M, Monson J P. Modulation of cortisol metabolism by the growth hormone receptor antagonist pegvisomant in patients with acromegaly.  J Clin Endocrinol Metab. 2001;  86 (7) 2989-2992
  • 49 Phillipov G, Palermo M, Shackleton C H. Apparent cortisone reductase deficiency: a unique form of hypercortisolism.  J Clin Endocrinol Metab. 1996;  81 (11) 3855-3860
  • 50 Jamieson A, Wallace A M, Andrew R. et al . Apparent cortisone reductase deficiency: a functional defect in 11beta-hydroxysteroid dehydrogenase type 1.  J Clin Endocrinol Metab. 1999;  84 (10) 3570-3574
  • 51 Nordenstrom A, Marcus C, Axelson M, Wedell A, Ritzen E M. Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of defective 11beta-hydroxysteroid dehydrogenase reductase activity.  J Clin Endocrinol Metab. 1999;  84 (4) 1210-1213
  • 52 Taylor N, Bartlett W A, Dawson D J. Cortisone reductase deficiency: Evidence for a new inborn error in metabolism of adrenal steroids.  J Endocrinol. 1984;  102S 89 (abstract)
  • 53 Savage M W, Barton R N, Doman T L, Horan M A, Robins A K, Taylor N. Increased metabolic clearance of cortisol in corticosteroid 11-reductase deficiency.  J Endocrinol. 1991;  129S 219 (abstract)
  • 54 Biason-Lauber A, Suter S L, Shackleton C H, Zachmann M. Apparent cortisone reductase deficiency: a rare cause of hyperandrogenemia and hypercortisolism.  Horm Res. 2000;  53 (5) 260-266
  • 55 Laing I, Adams J E, Wood P J, Taylor N F, Ray D W. Cortisone reductase deficiency (11 beta-hydroxysteroid dehydrogenase type 1) deficiency presenting with features of late onset congenital adrenal hyperplasia. 21st Joint meeting of the British Endocrine Societies 2002: P264 (abstract)
  • 56 Barf T, Vallgarda J, Emond R. et al . Arylsulfonamidothiazoles as a New Class of Potential Antidiabetic Drugs. Discovery of potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1.  J Med Chem. 2002;  45 (18) 3813-3815

Prof. P. M. Stewart, M.D., F.R.C.P., F.Med.Sci.

Division of Medical Sciences

University of Birmingham · Queen Elizabeth Hospital · Birmingham · United Kingdom B15 2TH ·

Phone: + 44 (121) 627 2380

Fax: + 44 (121) 121 627 2384

Email: P.M.Stewart@bham.ac.uk

    >