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Division of Nephrology and Hypertension, Department of Clinical Research, University of Berne, Berne, Switzerland
Submitted 17 September 2004 ; accepted in final form 16 December 2004
Dehydroepiandrosterone (DHEA) exerts beneficial effects on blood glucose levels and insulin sensitivity in obese rodents and humans, resembling the effects of peroxisome proliferator-activated receptor-
(PPAR) ligands and opposing those of glucocorticoids; however, the underlying mechanisms remain unclear. Glucocorticoids are reactivated locally by 11
-hydroxysteroid dehydrogenase type 1 (11-HSD1), which is currently considered as a promising target for the treatment of obesity and diabetes. Using differentiated 3T3-L1 adipocytes, we show that DHEA causes downregulation of 11-HSD1 and dose-dependent reduction of its oxoreductase activity. The effects of DHEA were comparable with those of the PPAR agonist rosiglitazone but not additive. Furthermore, DHEA reduced the expression of hexose-6-phosphate dehydrogenase, which stimulates the oxoreductase activity of 11-HSD1. These findings were confirmed in white adipose tissue and in liver from DHEA-treated C57BL/6J mice. Analysis of the transcription factors involved in the DHEA-dependent regulation of 11-HSD1 expression revealed a switch in CCAAT/enhancer-binding protein (C/EBP) expression. C/EBP
, a potent activator of 11-HSD1 gene transcription, was downregulated in 3T3-L1 adipocytes and in liver and adipose tissue of DHEA-treated mice, whereas C/EBP and C/EBP
, attenuating the effect of C/EBP, were unchanged or elevated. Our results further suggest a protective effect of DHEA on adipose tissue by upregulating PPAR and downregulating leptin, thereby contributing to the reduced expression of 11-HSD1. In summary, we provide evidence that some of the anti-diabetic effects of DHEA may be caused through inhibition of the local amplification of glucocorticoids by 11-HSD1 in adipose tissue.
11-hydroxysteroid dehydrogenase; adipocyte; obesity; diabetes
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