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Biological Chemistry

Editor-in-Chief: Brüne, Bernhard

Editorial Board Member: Buchner, Johannes / Ludwig, Stephan / Sies, Helmut / Turk, Boris / Wittinghofer, Alfred

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Sub-chronic administration of the 11β-HSD1 inhibitor, carbenoxolone, improves glucose tolerance and insulin sensitivity in mice with diet-induced obesity

Ashley Taylor1 / Nigel Irwin2 / Aine M. McKillop3 / Peter R. Flatt4 / Victor A. Gault5

1School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK

2School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK

3School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK

4School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK

5School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, Northern Ireland, UK

Corresponding author

Citation Information: Biological Chemistry. Volume 389, Issue 4, Pages 441–445, ISSN (Online) 14374315, ISSN (Print) 14316730, DOI: 10.1515/BC.2008.049, March 2008

Publication History

Received:
2007-10-26
Accepted:
2008-01-18
Published Online:
2008-03-27

Abstract

We have examined the metabolic effects of daily administration of carbenoxolone (CBX), a naturally occurring 11β-hydroxysteroid dehydrogenase (11β-HSD1) inhibitor, in mice with high fat diet-induced insulin resistance and obesity. Eight-week-old male Swiss TO mice placed on a synthetic high fat diet received daily intraperitoneal injections of either saline vehicle or CBX over a 16-day period. Daily administration of CBX had no effect on food intake, but significantly lowered body weight (1.1- to 1.2-fold) compared to saline-treated controls. Non-fasting plasma glucose levels were significantly decreased (1.6-fold) by CBX treatment on day 4 and remained lower throughout the treatment period. Circulating plasma corticosterone levels were not significantly altered by CBX treatment. Plasma glucose concentrations of CBX-treated mice were significantly reduced (1.4-fold) following an intraperitoneal glucose load compared with saline controls. Similarly, after 16-day treatment with CBX, exogenous insulin evoked a significantly greater reduction in glucose concentrations (1.4- to 1.8-fold). 11β-HSD1 gene expression was significantly down-regulated in liver, whereas glucocorticoid receptor gene expression was increased in both liver and adipose tissue following CBX treatment. The reduced body weight and improved metabolic control in mice with high fat diet-induced obesity upon daily CBX administration highlights the potential value of selective 11β-HSD1 inhibition as a new route for the treatment of type 2 diabetes and obesity.

Keywords: carbenoxolone (CBX); glucose tolerance; 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1); insulin sensitivity; obesity; type 2 diabetes

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