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

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Abstract
In liver and adipose tissue, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regenerates glucocorticoids from inactive 11-keto metabolites. Pharmacological inhibition or transgenic disruption of 11β-HSD1 attenuates glucocorticoid action and increases insulin sensitivity. Increased adipose 11β-HSD1 may also contribute to the metabolic complications of obesity. Here, we examine the effects of inhibition of 11β-HSDs with carbenoxolone in obese insulin-resistant Zucker rats, a strain in which tissue-specific dysregulation of 11β-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 11β-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 5β-reductase and had no significant effect on plasma corticosterone levels. In conclusion, carbenoxolone provides a model for liver-specific inhibition of 11β-HSD1, which results in improved lipid profile, in Zucker obese rats. Failure to inhibit 11β-HSD1 in adipose tissue and/or skeletal muscle may explain the lack of effect on glucose tolerance and obesity. Inhibition of adipose 11β-HSD1 is probably necessary to gain the maximum benefit of an 11β-HSD1 inhibitor.