17β-Estradiol inhibits 11β-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes

17 beta-Estradiol (E-2) serves as an anti-obesity steroid; however, the mechanism underlying this effect has not been fully clarified. The effect of E-2 on adipocytes opposes that of glucocorticoids, which potentiate adipogenesis and anabolic lipid metabolism. The key to the intracellular activation Of glucocorticoid in adipocytes is 11 beta-hydroxy-steroid dehydrogenase type 1 (11 beta-HSD1), which catalyses the production of active glucocorticoids (cortisol in humans and corticosterone in rodents) from inactive 11-keto steroids (cortisone in humans and 11-dehydro-corticosterone in rodents), Using differentiated 3T3-L1 adipocytes, we showed that E-2 inhibited 11 beta-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E-2 on 11 beta-HSD1 activity was observed within 5-10 min. Furthermore, acetylation or alpha-epimerization of 17-hydroxy group of E-2 attenuated the inhibitory effect on 11 beta-HSD1. These results indicate that the inhibition of 11 beta-HSD1 by E-2 depends oil neither all ER-dependent route, transcriptional pathway nor nonspecific fashion. Hexose-6-phosphate dehydrogenase, which provides the cofactor NADPH for full activation of 11 beta-HSD1, was unaffected by E-2. A kinetic study revealed that E-2 acted as a non-competitive inhibitor of 11 beta-HSD1. The inhibitory effect of E-2 on 11 beta-HSD1 was reproduced in adipocytes isolated front rat mesenteric fat depots. This is the first demonstration that E-2 inhibits 11 beta-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen. Journal of Endocrinology (2009) 202, 131-139