Is 11beta-hydroxysteroid dehydrogenase type 1 a therapeutic target? Effects of carbenoxolone in lean and obese Zucker rats.
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.
Livingstone
Dawn E W
DE
Endocrinology Unit, Department of Medical Sciences, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
Walker
Brian R
BR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology* / Q000627:therapeutic use; D004435:Eating / Q000187:drug effects*; D005951:Glucose Tolerance Test; D006913:Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects; D008055:Lipids / Q000097:blood; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000201:enzymology* / Q000503:physiopathology; D010088:Oxidoreductases / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D015430:Weight Gain / Q000187:drug effects
D008055:Lipids; D010088:Oxidoreductases; D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D002229:Carbenoxolone