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Vol. 305, Issue 1, 167-172, April 2003
-Hydroxysteroid Dehydrogenase Type 1 a Therapeutic
Target? Effects of Carbenoxolone in Lean and Obese Zucker Rats
Endocrinology Unit, Department of Medical Sciences, University of
Edinburgh, Western General Hospital, Edinburgh, United Kingdom
In liver and adipose tissue, 11
-hydroxysteroid dehydrogenase type 1 (11-HSD1) regenerates glucocorticoids from inactive 11-keto
metabolites. Pharmacological inhibition or transgenic disruption
of 11-HSD1 attenuates glucocorticoid action and increases insulin
sensitivity. Increased adipose 11-HSD1 may also contribute to the
metabolic complications of obesity. Here, we examine the effects of
inhibition of 11-HSDs with carbenoxolone in obese insulin-resistant
Zucker rats, a strain in which tissue-specific dysregulation of
11-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 11-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 5-reductase and had no
significant effect on plasma corticosterone levels. In conclusion,
carbenoxolone provides a model for liver-specific inhibition of
11-HSD1, which results in improved lipid profile, in Zucker obese
rats. Failure to inhibit 11-HSD1 in adipose tissue and/or skeletal
muscle may explain the lack of effect on glucose tolerance and obesity.
Inhibition of adipose 11-HSD1 is probably necessary to gain the
maximum benefit of an 11-HSD1 inhibitor.
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