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.

Excess glucocorticoids promote visceral obesity and insulin resistance. The main regulator of intracellular glucocorticoid levels are 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive glucocorticoid into bioactive glucocorticoid such as cortisol in humans and corticosterone in rodents; therefore, the inhibition of 11β-HSD1 has considerable therapeutic potential for metabolic diseases including obesity and diabetes. Benzofuran is a key structure in many biologically active compounds such as benzbromarone, malibatol A and ( )-liphagal. The aim of this study was to investigate the inhibitory effect of benzofuran derivatives on 11β-HSD1 in mesenteric adipose tissue from rodents. 11β-HSD1 activity was determined by incubation of rat mesenteric adipose tissue microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) with and without benzofuran derivatives (Compounds 1-14). The corti-

Epigallocatechin gallate (EGCG) in green tea is thought to be useful as an anti‐obesity compound since it has been shown to reduce diet‐induced obesity in mice, rats and humans. On the other hand, 11β‐hydroxysteroid dehydrogenase type 1 (11β‐HSD1) converts inactive glucocorticoid (GC) to active GC in the liver and adipose tissue. Activated GC plays an important role in the pathogenesis of central obesity. This study investigated the effect of EGCG on 11β‐HSD1 activity in rodent adipose tissue. Microsome (Mc) containing 11β‐HSD1 was prepared from rat mesenteric adipose depots. Then 11β‐HSD1 activity in Mc was determined in MOPS buffer containing 1 μM 11‐dehydrocorticosterone and varying concentrations of EGCG (NADPH‐regenerating system). After the addition of Mc, the reactants were incubated at 37°C for 60 min. Corticosterone produced in the medium was measured by HPLC. Significant inhibition of 11β‐HSD1 by EGCG (1–40 μM) was observed. Kinetic study demonstrated that EGCG acted as a non‐competitive inhibitor of 11β‐HSD1 with an IC50 of 2.5 μM. The inhibition of 11β‐HSD1 appeared within 60 min in a cell‐free system. These findings suggest that the most likely mechanism of 11β‐HSD1 inhibition by EGCG is via direct interaction between EGCG and 11β‐HSD1 enzyme, rather than via transcriptional pathway. The anti‐obesity effects of EGCG are attributed, at least in part, to the inhibition of 11β‐HSD1 activity in adipocytes.