title: 17Beta-estradiol inhibits 11beta-hydroxysteroid dehydrogenase type 1 activity in rodent adipocytes.
abstract: 17Beta-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 11beta-hydroxysteroid dehydrogenase type 1 (11beta-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 E(2) inhibited 11beta-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E(2) on 11beta-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 11beta-HSD1. These results indicate that the inhibition of 11beta-HSD1 by E(2) 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 11beta-HSD1, was unaffected by E(2). A kinetic study revealed that E(2) acted as a non-competitive inhibitor of 11beta-HSD1. The inhibitory effect of E(2) on 11beta-HSD1 was reproduced in adipocytes isolated from rat mesenteric fat depots. This is the first demonstration that E(2) inhibits 11beta-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen.
authors.affiliation: Department of Medical Biochemistry, Kobe Pharmaceutical University, Kobe, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Tagawa
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Yuda
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kubota
authors.forename: Midori
authors.initials: M
authors.lastname: Wakabayashi
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Daisuke
authors.initials: D
authors.lastname: Kiyonaga
authors.forename: Natsuko
authors.initials: N
authors.lastname: Mori
authors.forename: Erika
authors.initials: E
authors.lastname: Minamitani
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Masuzaki
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kobayashi
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors; D012377:Rodentia; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D011960:Receptors, Estrogen; D004958:Estradiol; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1