17b-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 11b-hydroxysteroid dehydrogenase type 1 (11b-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 11b-HSD1 activity. Estrogen receptor (ER) antagonists, ICI-182 780 and tamoxifen, failed to reverse this inhibition. A significant inhibitory effect of E 2 on 11b-HSD1 activity was observed within 5-10 min. Furthermore, acetylation or a-epimerization of 17-hydroxy group of E 2 attenuated the inhibitory effect on 11b-HSD1. These results indicate that the inhibition of 11b-HSD1 by E 2 depends on neither an ER-dependent route, transcriptional pathway nor nonspecific fashion. Hexose-6-phosphate dehydrogenase, which provides the cofactor NADPH for full activation of 11b-HSD1, was unaffected by E 2 . A kinetic study revealed that E 2 acted as a non-competitive inhibitor of 11b-HSD1. The inhibitory effect of E 2 on 11b-HSD1 was reproduced in adipocytes isolated from rat mesenteric fat depots. This is the first demonstration that E 2 inhibits 11b-HSD1, thereby providing a novel insight into the anti-obesity mechanism of estrogen.

Stress stimulates sympatho‐adrenomedullary activity and lipolysis in adipocytes. Increase in plasma free fatty acids has been demonstrated to be a major link between obesity and insulin resistance. However, there are many reports describing the anti‐obesity effect of estrogen. This study investigated the effect of estrogen on isoproterenol (ISO) activated lipolysis in murine adipocytes. ISO (5 μM) and 17β‐Estradiol (E2) was added to mature 3T3‐L1 adipocytes in 6 well plates. After 2 hr incubation at 37 °C in 5% CO2/95% air, the glycerol concentration in DMEM medium was measured. Effects of β2‐adrenoceptor inhibitor (yohimbine, 50 μM), phosphodiesterase inhibitor (cilostamide, 2 μM) and estrogen receptor blocker (tamoxifen, 10 μM) on the inhibitory effect of lipolysis of E2 were also tested. Further, effect of E2 on cAMP production and hormone sensitive lipase (HSL) activity in 3T3‐L1 adipocytes were investigated. E2 (5–50 μM) inhibited ISO activated lipolysis in 3T3‐L1 adipocytes dose‐dependently. Yohimbine, cilostamide and tamoxifen did not abolish the inhibitory effect of E2 on ISO activated lipolysis. E2 inhibited HSL activity, whereas E2 did not reverse the increased cAMP level induced by ISO stimulation. These results suggest that E2 exerts its inhibitory effect of ISO activated lipolysis by inhibition somewhere down‐stream of cAMP production but up‐stream of the HSL signaling pathway.