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Am J Physiol Endocrinol Metab 288: E957-E964, 2005. First published December 21, 2004; doi:10.1152/ajpendo.00442.2004
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Dehydroepiandrosterone inhibits the amplification of glucocorticoid action in adipose tissue

Galina Apostolova,* Roberto A. S. Schweizer,* Zoltan Balazs, Radina M. Kostadinova, and Alex Odermatt

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-{gamma} (PPAR{gamma}) ligands and opposing those of glucocorticoids; however, the underlying mechanisms remain unclear. Glucocorticoids are reactivated locally by 11{beta}-hydroxysteroid dehydrogenase type 1 (11{beta}-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{beta}-HSD1 and dose-dependent reduction of its oxoreductase activity. The effects of DHEA were comparable with those of the PPAR{gamma} agonist rosiglitazone but not additive. Furthermore, DHEA reduced the expression of hexose-6-phosphate dehydrogenase, which stimulates the oxoreductase activity of 11{beta}-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{beta}-HSD1 expression revealed a switch in CCAAT/enhancer-binding protein (C/EBP) expression. C/EBP{alpha}, a potent activator of 11{beta}-HSD1 gene transcription, was downregulated in 3T3-L1 adipocytes and in liver and adipose tissue of DHEA-treated mice, whereas C/EBP{beta} and C/EBP{delta}, attenuating the effect of C/EBP{alpha}, were unchanged or elevated. Our results further suggest a protective effect of DHEA on adipose tissue by upregulating PPAR{alpha} and downregulating leptin, thereby contributing to the reduced expression of 11{beta}-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{beta}-HSD1 in adipose tissue.

11{beta}-hydroxysteroid dehydrogenase; adipocyte; obesity; diabetes


Address for reprint requests and other correspondence: A. Odermatt, Division of Nephrology and Hypertension, Dept. of Clinical Research, Univ. of Berne, Freiburgstrasse 15, 3010 Berne, Switzerland (E-mail: alex.odermatt{at}dkf.unibe.ch)




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