Endocrine Abstracts (2006) 11 P406

Dehydroepiandrosterone inhibits differentiation, proliferation and 11β-hydroxysteroid dehydrogenase type 1 activity in human preadipocytes

J McNelis, IJ Bujalska, PM Stewart & W Arlt

Division of Medical Sciences, University of Birmingham, Birmingham, United Kingdom.

The adrenal steroid dehydroepiandrosterone (DHEA) has been shown in vivo, to mimic the effects of peroxosome proliferator-activated receptor (PPAR) ligands and oppose those of glucocorticoids, thus producing beneficial effects on insulin sensitivity and adipogenesis in obese and diabetic rodents. Furthermore, DHEA treatment has recently been shown to reduce subcutaneous and visceral fat in humans in vivo. However, the mechanism by which DHEA produces these anti-adipogenic effects remains to be elucidated. Glucocorticoids, which play a key role in regulating fat metabolism and distribution, are reactivated locally by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), expressed in adipocytes. Recent literature has shown that DHEA can significantly inhibit 11β-HSD1 activity in differentiated murine 3T3-L1 adipocytes, albeit at levels considered supraphysiological in humans. Utilizing a human adipocyte cell system stably expressing 11β-HSD1 (chub-s7) we have tested if these findings would be replicated in human cells treated with physiological concentrations of DHEA, irrespective of the innate differences between the rodent and human endocrine system. Fully differentiated chub-s7 cells were treated with physiological (10–1000 nM) and supraphysiological (25–100 μM) DHEA concentrations for 48 hours. Adipocyte differentiation, as assessed by 11β-HSD1 activity and the expression of early (lipoprotein lipase) and terminal (G6PHD) differentiation markers, decreased markedly when treated with 25–100 μM DHEA. In contrast lower concentrations had no effect on differentiation. Similar findings were seen when chub-s7 cells were differentiated in the presence of DHEA. To investigate the effect of DHEA on proliferation preconfluent proliferating Chub-s7 cells were incubated for either 24, 72 or 96 hours with DHEA. Again, higher DHEA concentrations had a marked effect on proliferation while physiologic concentrations had no effect. In summary, DHEA inhibits proliferation and differentiation of human adipocytes, possibly via the observed significant inhibition of 11β-HSD1 activity. However, this effect was only seen when employing supraphysiological DHEA concentrations.

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