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This Article Full Text Full Text (PDF) All Versions of this Article: JOE-09-0021v1 202/1/131    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Tagawa, N. Articles by Kobayashi, Y. Search for Related Content PubMed PubMed Citation Articles by Tagawa, N. Articles by Kobayashi, Y.

Department of Medical Biochemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan
¹ Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan

(Correspondence should be addressed to Y Kobayashi; Email: yoshi{at}kobepharma-u.ac.jp)

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 -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.