title: 11Beta-hydroxysteroid dehydrogenase type 1 in differentiating omental human preadipocytes: from de-activation to generation of cortisol.
abstract: In humans, glucocorticoids are important regulators of adipose tissue distribution and function but circulating cortisol concentrations are normal in most patients with obesity. However, intracellular glucocorticoid levels can be modified by a microsomal enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) expressed mainly in the liver and adipose tissue. Locally generated cortisol within human adipose tissue can induce preadipocyte differentiation, but the relationship between 11beta-HSD1 expression and adipogenesis is unknown. Our present study has shown that in intact, undifferentiated omental (OM) but not subcutaneous (SC) preadipocytes, 11beta-HSD1 acts primarily as a dehydrogenase inactivating cortisol to cortisone. When preadipocytes become "committed" to adipocyte differentiation, oxo-reductase activity predominates generating cortisol. Since glucocorticoids are not only essential for OM preadipocyte differentiation but also inhibit cell proliferation, we postulate that 11beta-HSD1 dehydrogenase activity in "uncommitted" OM preadipocytes may provide an autocrine mechanism to protect preadipocytes from differentiation, in turn facilitating their proliferation. Once early differentiation is initiated, a "switch" to 11beta-HSD1 oxo-reductase activity generates cortisol, thus promoting adipogenesis. The differences in set-point of 11beta-HSD1 activity between OM and SC human adipose tissue may be an important factor in the pathogenesis of visceral obesity.
authors.affiliation: Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham B15 2TH, UK.
authors.forename: Iwona J
authors.initials: IJ
authors.lastname: Bujalska
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Walker
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D017667:Adipocytes / Q000166:cytology / Q000201:enzymology*; D002454:Cell Differentiation / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis*; D006913:Hydroxysteroid Dehydrogenases / Q000378:metabolism*; D009852:Omentum / Q000166:cytology* / Q000201:enzymology*; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*
chemical_list: D006913:Hydroxysteroid Dehydrogenases; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C468386:HSD11B1 protein, human; D006854:Hydrocortisone