title: Preadipocyte 11beta-hydroxysteroid dehydrogenase type 1 is a keto-reductase and contributes to diet-induced visceral obesity in vivo.
abstract: Glucocorticoid excess promotes visceral obesity and cardiovascular disease. Similar features are found in the highly prevalent metabolic syndrome in the absence of high levels of systemic cortisol. Although elevated activity of the glucocorticoid-amplifying enzyme 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) within adipocytes might explain this paradox, the potential role of 11beta-HSD1 in preadipocytes is less clear; human omental adipose stromal vascular (ASV) cells exhibit 11beta-dehydrogenase activity (inactivation of glucocorticoids) probably due to the absence of cofactor provision by hexose-6-phosphate dehydrogenase. To clarify the depot-specific impact of 11beta-HSD1, we assessed whether preadipocytes in ASV from mesenteric (as a representative of visceral adipose tissue) and sc tissue displayed 11beta-HSD1 activity in mice. 11beta-HSD1 was highly expressed in freshly isolated ASV cells, predominantly in preadipocytes. 11beta-HSD1 mRNA and protein levels were comparable between ASV and adipocyte fractions in both depots. 11beta-HSD1 was an 11beta-reductase, thus reactivating glucocorticoids in ASV cells, consistent with hexose-6-phosphate dehydrogenase mRNA expression. Unexpectedly, glucocorticoid reactivation was higher in intact mesenteric ASV cells despite a lower expression of 11beta-HSD1 mRNA and protein (homogenate activity) levels than sc ASV cells. This suggests a novel depot-specific control over 11beta-HSD1 enzyme activity. In vivo, high-fat diet-induced obesity was accompanied by increased visceral fat preadipocyte differentiation in wild-type but not 11beta-HSD1(-/-) mice. The results suggest that 11beta-HSD1 reductase activity is augmented in mouse mesenteric preadipocytes where it promotes preadipocyte differentiation and contributes to visceral fat accumulation in obesity.
authors.affiliation: C3.08, Endocrinology Unit, Center for Cardiovascular Sciences, The Queen's Medical Research Institute, 47 Little France Crescent, University of Edinburgh, New Royal Infirmary, Edinburgh, United Kingdom.
authors.forename: R A
authors.initials: RA
authors.lastname: De Sousa Peixoto
authors.forename: S
authors.initials: S
authors.lastname: Turban
authors.forename: J H
authors.initials: JH
authors.lastname: Battle
authors.forename: K E
authors.initials: KE
authors.lastname: Chapman
authors.forename: J R
authors.initials: JR
authors.lastname: Seckl
authors.forename: N M
authors.initials: NM
authors.lastname: Morton
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000032:analysis / Q000235:genetics / Q000502:physiology*; D017667:Adipocytes / Q000201:enzymology*; D000818:Animals; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000032:analysis; D004041:Dietary Fats / Q000008:administration & dosage; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology*; D012333:RNA, Messenger / Q000032:analysis; D013234:Stem Cells / Q000201:enzymology*
chemical_list: D004041:Dietary Fats; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1