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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 7 3330-3336
Copyright © 2002 by The Endocrine Society

Other Original Articles

Tissue-Specific Changes in Peripheral Cortisol Metabolism in Obese Women: Increased Adipose 11ß-Hydroxysteroid Dehydrogenase Type 1 Activity

Eva Rask, Brian R. Walker, Stefan Söderberg, Dawn E. W. Livingstone, Mats Eliasson, Owe Johnson, Ruth Andrew and Tommy Olsson

Department of Public Health and Clinical Medicine, Umeå University Hospital (E.R., S.S., M.E., O.J., T.O.), Umeå, Sweden 90185; and Department of Medical Sciences, University of Edinburgh (R.A., D.E.W.L., B.R.W.), Western General Hospital, Edinburgh, United Kingdom EH4 2XU

Address all correspondence and requests for reprints to: Prof. Brian R. Walker, University of Edinburgh, Endocrinology Unit, Western General Hospital, Edinburgh, United Kingdom EH4 2XU. E-mail address: . b.walker{at}ed.ac.uk

Abstract

Cushing’s syndrome and the metabolic syndrome share clinical similarities. Reports of alterations in the hypothalamic-pituitary-adrenal (HPA) axis are inconsistent, however, in the metabolic syndrome. Recent data highlight the importance of adipose 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1), which regenerates cortisol from cortisone and, when overexpressed in fat, produces central obesity and glucose intolerance. Here we assessed the HPA axis and 11ß-HSD1 activity in women with moderate obesity and insulin resistance.

Forty women were divided into tertiles according to body mass index (BMI; median, 22.0, 27.5, and 31.4, respectively). Serum cortisol levels were measured after iv CRH, low dose dexamethasone suppression, and oral cortisone administration. Urinary cortisol metabolites were measured in a 24-h sample. A sc abdominal fat biopsy was obtained in 14 participants for determination of 11ß-HSD type 1 activity in vitro.

Higher BMI was associated with higher total cortisol metabolite excretion (r = 0.49; P < 0.01), mainly due to increased 5{alpha}- and, to a lesser extent, 5ß-tetrahydrocortisol excretion, but no difference in plasma cortisol basally, after dexamethasone, or after CRH, and only a small increase in the ACTH response to CRH. Hepatic 11ß-HSD1 conversion of oral cortisone to cortisol was impaired in obese women (area under the curve, 147,736 ± 28,528, 115,903 ± 26,032, and 90,460 ± 18,590 nmol/liter·min; P < 0.001). However, 11ß-HSD activity in adipose tissue was positively correlated with BMI (r = 0.55; P < 0.05).

In obese females increased reactivation of glucocorticoids in fat may contribute to the characteristics of the metabolic syndrome. Increased inactivation of cortisol in liver may be responsible for compensatory activation of the HPA axis. These alterations in cortisol metabolism may be a basis for novel therapeutic strategies to reduce obesity-related complications.




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Altered Cortisol Metabolism in Polycystic Ovary Syndrome: Insulin Enhances 5{alpha}-Reduction But Not the Elevated Adrenal Steroid Production Rates
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M. Ehrhart-Bornstein, V. Lamounier-Zepter, A. Schraven, J. Langenbach, H. S. Willenberg, A. Barthel, H. Hauner, S. M. McCann, W. A. Scherbaum, and S. R. Bornstein
Human adipocytes secrete mineralocorticoid-releasing factors
PNAS, November 25, 2003; 100(24): 14211 - 14216.
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P. Alberts, C. Nilsson, G. Selen, L. O. M. Engblom, N. H. M. Edling, S. Norling, G. Klingstrom, C. Larsson, M. Forsgren, M. Ashkzari, et al.
Selective Inhibition of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Improves Hepatic Insulin Sensitivity in Hyperglycemic Mice Strains
Endocrinology, November 1, 2003; 144(11): 4755 - 4762.
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Scand J Public Health, November 1, 2003; 31(61_suppl): 85 - 91.
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J. Westerbacka, H. Yki-Jarvinen, S. Vehkavaara, A.-M. Hakkinen, R. Andrew, D. J. Wake, J. R. Seckl, and B. R. Walker
Body Fat Distribution and Cortisol Metabolism in Healthy Men: Enhanced 5{beta}-Reductase and Lower Cortisol/Cortisone Metabolite Ratios in Men with Fatty Liver
J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4924 - 4931.
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D. J. Wake, E. Rask, D. E. W. Livingstone, S. Soderberg, T. Olsson, and B. R. Walker
Local and Systemic Impact of Transcriptional Up-Regulation of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue in Human Obesity
J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 3983 - 3988.
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C. Mattsson, M. Lai, J. Noble, E. McKinney, J. L. Yau, J. R. Seckl, and B. R. Walker
Obese Zucker Rats Have Reduced Mineralocorticoid Receptor and 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression in Hippocampus--Implications for Dysregulation of the Hypothalamic-Pituitary-Adrenal Axis in Obesity
Endocrinology, July 1, 2003; 144(7): 2997 - 3003.
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R. S. Lindsay, D. J. Wake, S. Nair, J. Bunt, D. E. W. Livingstone, P. A. Permana, P. A. Tataranni, and B. R. Walker
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., June 1, 2003; 88(6): 2738 - 2744.
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B. R. Walker and R. Andrew
Cortisol Metabolism in Type 2 Diabetes
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2951 - 2952.
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Y. Liu, Y. Nakagawa, Y. Wang, R. Li, X. Li, T. Ohzeki, and T. C. Friedman
Leptin Activation of Corticosterone Production in Hepatocytes May Contribute to the Reversal of Obesity and Hyperglycemia in Leptin-Deficient ob/ob Mice
Diabetes, June 1, 2003; 52(6): 1409 - 1416.
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J. W. Tomlinson, N. Crabtree, P. M. S. Clark, G. Holder, A. A. Toogood, C. H. L. Shackleton, and P. M. Stewart
Low-Dose Growth Hormone Inhibits 11{beta}-Hydroxysteroid Dehydrogenase Type 1 but Has No Effect upon Fat Mass in Patients with Simple Obesity
J. Clin. Endocrinol. Metab., May 1, 2003; 88(5): 2113 - 2118.
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D. E. W. Livingstone and B. R. Walker
Is 11beta -Hydroxysteroid Dehydrogenase Type 1 a Therapeutic Target? Effects of Carbenoxolone in Lean and Obese Zucker Rats
J. Pharmacol. Exp. Ther., April 1, 2003; 305(1): 167 - 172.
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J.G. Dolfing, K.E. Tucker, C.M. Lem, J. Uittenbogaart, J.C. Verzijl, and D.H. Schweitzer
Low 11-deoxycortisol to cortisol conversion reflects extra-adrenal factors in the majority of women with normo-gonadotrophic normo-estrogenic infertility
Hum. Reprod., February 1, 2003; 18(2): 333 - 337.
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R. C. Andrews, O. Rooyackers, and B. R. Walker
Effects of the 11{beta}-Hydroxysteroid Dehydrogenase Inhibitor Carbenoxolone on Insulin Sensitivity in Men with Type 2 Diabetes
J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 285 - 291.
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11{beta}-Hydroxysteroid Dehydrogenase Activity in Hypothalamic Obesity
J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 379 - 384.
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R. C. Andrews, O. Herlihy, D. E. W. Livingstone, R. Andrew, and B. R. Walker
Abnormal Cortisol Metabolism and Tissue Sensitivity to Cortisol in Patients with Glucose Intolerance
J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5587 - 5593.
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Adiposity and Diabetes
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