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Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom EH4 2XU
Address all correspondence and requests for reprints to: Dr. Brian R. Walker, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom EH4 2X. E-mail: b.walker{at}ed.ac.uk
The role of glucocorticoids in obesity is poorly understood.
Observations in obese men suggest enhanced inactivation of cortisol by
5
-reductase and altered reactivation of cortisone to cortisol by
11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1). These changes in
glucocorticoid metabolism may influence corticosteroid receptor
activation and feedback regulation of the
hypothalamic-pituitary-adrenal axis (HPA). We have compared
corticosterone metabolism in vivo and in
vitro in male obese and lean Zucker rats, aged 9 weeks (n
= 8/group). Steroids were measured in 72-h urine and 0900 h trunk
blood samples. 5-Reductase type 1 and 11ßHSD activities were
assessed in dissected tissues. Obese animals were
hypercorticosteronemic and excreted more total corticosterone
metabolites (2264 ± 623 vs. 388 ± 144 ng/72
h; P = 0.003), with a greater proportion being
5-reduced or 11-oxidized. 11-Dehydrocorticosterone was also elevated
in plasma (73 ± 9 vs. 18 ± 2 nM;
P = 0.001) and urine (408 ± 111
vs. <28 ng/72 h; P = 0.01). In
liver of obese rats, 5-reductase type 1 activity was greater
(20.6 ± 2.7% vs. 14.1 ± 1.5%;
P < 0.04), but 11ßHSD1 activity (maximum
velocity, 3.43 ± 0.56 vs. 6.57 ± 1.13
nmol/min/mg protein; P = 0.01) and messenger RNA
levels (0.56 ± 0.08 vs. 1.03 ± 0.15;
P = 0.02) were lower. In contrast, in obese rats,
11ßHSD1 activity was not different in skeletal muscle and sc fat and
was higher in omental fat (36.4 ± 6.2 vs.
19.2 ± 6.6; P = 0.01), whereas 11ßHSD2
activity was higher in kidney (16.7 ± 0.6% vs.
11.3 ± 1.5%; P = 0.01).
We conclude that greater inactivation of glucocorticoids by
5-reductase in liver and 11ßHSD2 in kidney combined with impaired
reactivation of glucocorticoids by 11ßHSD1 in liver may increase the
MCR of glucocorticoids and decrease local glucocorticoid concentrations
at these sites. By contrast, enhanced 11ßHSD1 in omental adipose
tissue may increase local glucocorticoid receptor activation and
promote obesity.
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text]
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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. [Abstract] [Full Text] [PDF]
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C. Wotus and W. C. Engeland Differential regulation of adrenal corticosteroids after restriction-induced drinking in rats Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2003; 284(1): R183 - R191. [Abstract] [Full Text] [PDF]
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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. [Abstract] [Full Text] [PDF]
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J. W. Tomlinson, B. Sinha, I. Bujalska, M. Hewison, and P. M. Stewart Expression of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue Is Not Increased in Human Obesity J. Clin. Endocrinol. Metab., December 1, 2002; 87(12): 5630 - 5635. [Abstract] [Full Text] [PDF]
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N. Draper, S. M. Echwald, G. G. Lavery, E. A. Walker, R. Fraser, E. Davies, T. I. A. Sorensen, A. Astrup, J. Adamski, M. Hewison, et al. Association Studies between Microsatellite Markers within the Gene Encoding Human 11{beta}-Hydroxysteroid Dehydrogenase Type 1 and Body Mass Index, Waist to Hip Ratio, and Glucocorticoid Metabolism J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4984 - 4990. [Abstract] [Full Text] [PDF]
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T. M. Stulnig, U. Oppermann, K. R. Steffensen, G. U. Schuster, and J.-A. Gustafsson Liver X Receptors Downregulate 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Expression and Activity Diabetes, August 1, 2002; 51(8): 2426 - 2433. [Abstract] [Full Text] [PDF]
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E. Rask, B. R. Walker, S. Soderberg, D. E. W. Livingstone, M. Eliasson, O. Johnson, R. Andrew, and T. Olsson Tissue-Specific Changes in Peripheral Cortisol Metabolism in Obese Women: Increased Adipose 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3330 - 3336. [Abstract] [Full Text] [PDF]
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K. E. Sheppard and D. J. Autelitano 11{beta}-Hydroxysteroid Dehydrogenase 1 Transforms 11-Dehydrocorticosterone into Transcriptionally Active Glucocorticoid in Neonatal Rat Heart Endocrinology, January 1, 2002; 143(1): 198 - 204. [Abstract] [Full Text] [PDF]
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 H. Masuzaki, J. Paterson, H. Shinyama, N. M. Morton, J. J. Mullins, J. R. Seckl, and J. S. Flier A Transgenic Model of Visceral Obesity and the Metabolic Syndrome Science, December 7, 2001; 294(5549): 2166 - 2170. [Abstract] [Full Text] [PDF]
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J. W. Tomlinson, J. Moore, M. S. Cooper, I. Bujalska, M. Shahmanesh, C. Burt, A. Strain, M. Hewison, and P. M. Stewart Regulation of Expression of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Adipose Tissue: Tissue-Specific Induction by Cytokines Endocrinology, May 1, 2001; 142(5): 1982 - 1989. [Abstract] [Full Text]
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J. R. Seckl and B. R. Walker Minireview: 11{beta}-Hydroxysteroid Dehydrogenase Type 1-- A Tissue-Specific Amplifier of Glucocorticoid Action Endocrinology, April 1, 2001; 142(4): 1371 - 1376. [Abstract] [Full Text]
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N. M. Morton, M. C. Holmes, C. Fievet, B. Staels, A. Tailleux, J. J. Mullins, and J. R. Seckl Improved Lipid and Lipoprotein Profile, Hepatic Insulin Sensitivity, and Glucose Tolerance in 11beta -Hydroxysteroid Dehydrogenase Type 1 Null Mice J. Biol. Chem., October 26, 2001; 276(44): 41293 - 41300. [Abstract] [Full Text] [PDF]
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