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

Abstract

17β-Estradiol (E2) serves as an anti-obesity steroid; however, the mechanism underlying this effect has not been fully clarified. The effect of E2 on adipocytes opposes that of glucocorticoids, which potentiate adipogenesis and anabolic lipid metabolism. The key to the intracellular activation of glucocorticoid in adipocytes is 11β-hydroxysteroid dehydrogenase type 1 (11β-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-dehydrocorticosterone in rodents). Using differentiated 3T3-L1 adipocytes, we showed that E2 inhibited 11β-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E2 on 11β-HSD1 activity was observed within 5–10 min. Furthermore, acetylation or α-epimerization of 17-hydroxy group of E2 attenuated the inhibitory effect on 11β-HSD1. These results indicate that the inhibition of 11β-HSD1 by E2 depends on neither an ER-dependent route, transcriptional pathway nor non-specific fashion. Hexose-6-phosphate dehydrogenase, which provides the cofactor NADPH for full activation of 11β-HSD1, was unaffected by E2. A kinetic study revealed that E2 acted as a non-competitive inhibitor of 11β-HSD1. The inhibitory effect of E2 on 11β-HSD1 was reproduced in adipocytes isolated from rat mesenteric fat depots. This is the first demonstration that E2 inhibits 11β-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen.