title: A novel selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitor prevents human adipogenesis.
abstract: Glucocorticoid excess increases fat mass, preferentially within omental depots; yet circulating cortisol concentrations are normal in most patients with metabolic syndrome (MS). At a pre-receptor level, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates cortisol from cortisone locally within adipose tissue, and inhibition of 11beta-HSD1 in liver and adipose tissue has been proposed as a novel therapy to treat MS by reducing hepatic glucose output and adiposity. Using a transformed human subcutaneous preadipocyte cell line (Chub-S7) and human primary preadipocytes, we have defined the role of glucocorticoids and 11beta-HSD1 in regulating adipose tissue differentiation. Human cells were differentiated with 1.0 microM cortisol (F), or cortisone (E) with or without 100 nM of a highly selective 11beta-HSD1 inhibitor PF-877423. 11beta-HSD1 mRNA expression increased across adipocyte differentiation (P<0.001, n=4), which was paralleled by an increase in 11beta-HSD1 oxo-reductase activity (from nil on day 0 to 5.9+/-1.9 pmol/mg per h on day 16, P<0.01, n=7). Cortisone enhanced adipocyte differentiation; fatty acid-binding protein 4 expression increased 312-fold (P<0.001) and glycerol-3-phosphate dehydrogenase 47-fold (P<0.001) versus controls. This was abolished by co-incubation with PF-877423. In addition, cellular lipid content decreased significantly. These findings were confirmed in the primary cultures of human subcutaneous preadipocytes. The increase in 11beta-HSD1 mRNA expression and activity is essential for the induction of human adipogenesis. Blocking adipogenesis with a novel and specific 11beta-HSD1 inhibitor may represent a novel approach to treat obesity in patients with MS.
authors.affiliation: Division of Medical Sciences, The Medical School, Institute of Biomedical Research, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: I J
authors.initials: IJ
authors.lastname: Bujalska
authors.forename: L L
authors.initials: LL
authors.lastname: Gathercole
authors.forename: J W
authors.initials: JW
authors.lastname: Tomlinson
authors.forename: C
authors.initials: C
authors.lastname: Darimont
authors.forename: J
authors.initials: J
authors.lastname: Ermolieff
authors.forename: A N
authors.initials: AN
authors.lastname: Fanjul
authors.forename: P A
authors.initials: PA
authors.lastname: Rejto
authors.forename: P M
authors.initials: PM
authors.lastname: Stewart
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D050156:Adipogenesis / Q000187:drug effects*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D050556:Fatty Acid-Binding Proteins / Q000235:genetics; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D024821:Metabolic Syndrome / Q000209:etiology; D047495:PPAR gamma / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D004791:Enzyme Inhibitors; C493410:FABP4 protein, human; D050556:Fatty Acid-Binding Proteins; D005938:Glucocorticoids; D047495:PPAR gamma; D012333:RNA, Messenger; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1