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1 Division of Nephrology and Hypertension, University of Berne, Berne, Switzerland
* To whom correspondence should be addressed. E-mail: alex.odermatt{at}dkf.unibe.ch.
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 remained
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 down-regulation 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 (H6PDH), 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 down-regulated 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
up-regulating PPAR and down-regulating 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.
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