title: Alternative mechanism for anti-obesity effect of dehydroepiandrosterone: possible contribution of 11β-hydroxysteroid dehydrogenase type 1 inhibition in rodent adipose tissue.
abstract: Dehydroepiandrosterone (DHEA) has been suggested to have an anti-obesity effect; however, the mechanism underlying this effect remains unclear. The effect of DHEA on adipocytes opposes that of glucocorticoids, which potentiate adipogenesis. The key to the intracellular activation of glucocorticoids 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 an inactive 11-keto form (cortisone in humans and 11-dehydrocorticosterone in rodents). In humans and rodents, intracellular glucocorticoid reactivation is exaggerated in obese adipose tissue. Using differentiated 3T3-L1 adipocytes, we demonstrated that DHEA inhibited about 15.6% of 11β-HSD1 activity at a concentration of 1 μM within 10min. Inhibition was also observed in a cell-free system composed of microsomes prepared from rat adipose tissue and NADPH, a coenzyme of 11β-HSD1. A kinetic study revealed that DHEA acted as a non-competitive inhibitor of 11β-HSD1. Moreover, conversion from DHEA to estrogens was not observed by sensitive semi-micro HPLC equipped with electrochemical detector. These results indicate that the inhibition of 11β-HSD1 by DHEA depends on neither the transcriptional pathway nor the nonspecific manner. This is the first demonstration that the anti-obesity effect of DHEA is exerted by non-transcriptional inhibition of 11β-HSD1 in rodent adipocytes.
authors.affiliation: Department of Medical Biochemistry, Kobe Pharmaceutical University, 4-19-1 Motoyamakita-machi, Higashinada-ku, Kobe 658-8558, Japan. t-noriko@kobepharma-u.ac.jp
authors.forename: Noriko
authors.initials: N
authors.lastname: Tagawa
authors.forename: Erika
authors.initials: E
authors.lastname: Minamitani
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yamaguchi
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; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D000818:Animals; D019440:Anti-Obesity Agents / Q000378:metabolism / Q000494:pharmacology*; D003687:Dehydroepiandrosterone / Q000378:metabolism / Q000494:pharmacology*; D019314:Dehydroepiandrosterone Sulfate / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats
chemical_list: D019440:Anti-Obesity Agents; D004791:Enzyme Inhibitors; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1