JPET

Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
QUICK SEARCH:   [advanced]


     

Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on January 21, 2003; DOI: 10.1124/jpet.102.044842

This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
jpet.102.044842v1
305/1/167    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Livingstone, D. E. W.
Right arrow Articles by Walker, B. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Livingstone, D. E. W.
Right arrow Articles by Walker, B. R.

Vol. 305, Issue 1, 167-172, April 2003

Is 11beta -Hydroxysteroid Dehydrogenase Type 1 a Therapeutic Target? Effects of Carbenoxolone in Lean and Obese Zucker Rats

Dawn E. W. Livingstone and Brian R. Walker

Endocrinology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom

In liver and adipose tissue, 11beta -hydroxysteroid dehydrogenase type 1 (11beta -HSD1) regenerates glucocorticoids from inactive 11-keto metabolites. Pharmacological inhibition or transgenic disruption of 11beta -HSD1 attenuates glucocorticoid action and increases insulin sensitivity. Increased adipose 11beta -HSD1 may also contribute to the metabolic complications of obesity. Here, we examine the effects of inhibition of 11beta -HSDs with carbenoxolone in obese insulin-resistant Zucker rats, a strain in which tissue-specific dysregulation of 11beta -HSD1 (increased in adipose, decreased in liver) mirrors changes in human obesity. Six-week-old male rats were treated orally with carbenoxolone (50 mg/kg/day) or water (1 ml/kg/day) for 3 weeks. Carbenoxolone inhibited 11beta -HSD1 activity in liver (25 ± 3 versus 52 ± 2% conversion in lean; 18 ± 3 versus 35 ± 3% in obese; p < 0.01) but not in adipose tissue or skeletal muscle. Carbenoxolone had no effect on weight gain or food intake, did not affect plasma glucose during an oral glucose tolerance test, and increased the plasma insulin response to glucose. However, high-density lipoprotein cholesterol was increased by carbenoxolone in obese animals (1.52 ± 0.24 versus 1.21 ± 0.26 mM; p < 0.03). Carbenoxolone did not inhibit hepatic inactivation of glucocorticoid by 5beta -reductase and had no significant effect on plasma corticosterone levels. In conclusion, carbenoxolone provides a model for liver-specific inhibition of 11beta -HSD1, which results in improved lipid profile, in Zucker obese rats. Failure to inhibit 11beta -HSD1 in adipose tissue and/or skeletal muscle may explain the lack of effect on glucose tolerance and obesity. Inhibition of adipose 11beta -HSD1 is probably necessary to gain the maximum benefit of an 11beta -HSD1 inhibitor.

0022-3565/03/3051-0167$07.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics


This article has been cited by other articles:


Home page
 J Mol EndocrinolHome page
Y. Liu, Y. Nakagawa, Y. Wang, L. Liu, H. Du, W. Wang, X. Ren, K. Lutfy, and T. C Friedman
Reduction of hepatic glucocorticoid receptor and hexose-6-phosphate dehydrogenase expression ameliorates diet-induced obesity and insulin resistance in mice
J. Mol. Endocrinol., August 1, 2008; 41(2): 53 - 64.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
D. P Macfarlane, S. Forbes, and B. R Walker
Glucocorticoids and fatty acid metabolism in humans: fuelling fat redistribution in the metabolic syndrome
J. Endocrinol., May 1, 2008; 197(2): 189 - 204.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
A. M. Nuotio-Antar, D. L. Hachey, and A. H. Hasty
Carbenoxolone treatment attenuates symptoms of metabolic syndrome and atherogenesis in obese, hyperlipidemic mice
Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1517 - E1528.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
D. Qi and B. Rodrigues
Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism
Am J Physiol Endocrinol Metab, March 1, 2007; 292(3): E654 - E667.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
S. Nammi, K. Dembele, and B. L. G. Nyomba
Increased 11beta-hydroxysteroid dehydrogenase type-1 and hexose-6-phosphate dehydrogenase in liver and adipose tissue of rat offspring exposed to alcohol in utero
Am J Physiol Regulatory Integrative Comp Physiol, March 1, 2007; 292(3): R1101 - R1109.
[Abstract] [Full Text] [PDF]

Home page
 J EndocrinolHome page
K Vagnerova, M Kverka, P Klusonova, P Ergang, I Miksik, H Tlaskalova-Hogenova, and J Pacha
Intestinal inflammation modulates expression of 11{beta}-hydroxysteroid dehydrogenase in murine gut.
J. Endocrinol., November 1, 2006; 191(2): 497 - 503.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
A. Hermanowski-Vosatka, J. M. Balkovec, K. Cheng, H. Y. Chen, M. Hernandez, G. C. Koo, C. B. Le Grand, Z. Li, J. M. Metzger, S. S. Mundt, et al.
11{beta}-HSD1 inhibition ameliorates metabolic syndrome and prevents progression of atherosclerosis in mice
J. Exp. Med., August 15, 2005; 202(4): 517 - 527.
[Abstract] [Full Text] [PDF]

Home page
 J Mol EndocrinolHome page
I. J Bujalska, N. Draper, Z. Michailidou, J. W Tomlinson, P. C White, K. E Chapman, E. A Walker, and P. M Stewart
Hexose-6-phosphate dehydrogenase confers oxo-reductase activity upon 11{beta}-hydroxysteroid dehydrogenase type 1
J. Mol. Endocrinol., June 1, 2005; 34(3): 675 - 684.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
K. N. Hewitt, E. A. Walker, and P. M. Stewart
Minireview: Hexose-6-Phosphate Dehydrogenase and Redox Control of 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Activity
Endocrinology, June 1, 2005; 146(6): 2539 - 2543.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
G. Apostolova, R. A. S. Schweizer, Z. Balazs, R. M. Kostadinova, and A. Odermatt
Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue
Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E957 - E964.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
T. C. Sandeep, R. Andrew, N. Z.M. Homer, R. C. Andrews, K. Smith, and B. R. Walker
Increased In Vivo Regeneration of Cortisol in Adipose Tissue in Human Obesity and Effects of the 11{beta}-Hydroxysteroid Dehydrogenase Type 1 Inhibitor Carbenoxolone
Diabetes, March 1, 2005; 54(3): 872 - 879.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. A. S. Schweizer, M. Zurcher, Z. Balazs, B. Dick, and A. Odermatt
Rapid Hepatic Metabolism of 7-Ketocholesterol by 11{beta}-Hydroxysteroid Dehydrogenase Type 1: SPECIES-SPECIFIC DIFFERENCES BETWEEN THE RAT, HUMAN, AND HAMSTER ENZYME
J. Biol. Chem., April 30, 2004; 279(18): 18415 - 18424.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
N. M. Morton, J. M. Paterson, H. Masuzaki, M. C. Holmes, B. Staels, C. Fievet, B. R. Walker, J. S. Flier, J. J. Mullins, and J. R. Seckl
Novel Adipose Tissue-Mediated Resistance to Diet-Induced Visceral Obesity in 11{beta}-Hydroxysteroid Dehydrogenase Type 1-Deficient Mice
Diabetes, April 1, 2004; 53(4): 931 - 938.
[Abstract] [Full Text] [PDF]

Home page
 DiabetesHome page
K. R. Steffensen and J.-A. Gustafsson
Putative Metabolic Effects of the Liver X Receptor (LXR)
Diabetes, February 1, 2004; 53(90001): S36 - 42.
[Abstract] [Full Text]

Home page
 Recent Prog Horm ResHome page
J. R. Seckl, N. M. Morton, K. E. Chapman, and B. R. Walker
Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase in Adipose Tissue
Recent Prog. Horm. Res., January 1, 2004; 59(1): 359 - 393.
[Abstract] [Full Text]

Home page
 J. Clin. Endocrinol. Metab.Home page
D. S. Weigle
Pharmacological Therapy of Obesity: Past, Present, and Future
J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2462 - 2469.
[Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] [Contents]
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2003 by the American Society for Pharmacology and Experimental Therapeutics.