title: 11-Dehydrocorticosterone causes metabolic syndrome, which is prevented when 11β-HSD1 is knocked out in livers of male mice.
abstract: Metabolic syndrome is growing in importance with the rising levels of obesity, type 2 diabetes, and insulin resistance. Metabolic syndrome shares many characteristics with Cushing's syndrome, which has led to investigation of the link between excess glucocorticoids and metabolic syndrome. Indeed, increased glucocorticoids from intracellular regeneration by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) drives insulin resistance and increases adiposity, but these metabolic changes are assumed to be due to increased circulating glucocorticoids. We hypothesized that increasing the substrate for 11β-HSD1 (11-dehydrocorticosterone, 11-DHC) would adversely affect metabolic parameters. We found that chronic administration of 11-DHC to male C57BL/6J mice resulted in increased circulating glucocorticoids, and down-regulation of the hypothalamic-pituitary-adrenal axis. This elevated 11β-HSD1-derived corticosterone led to increased body weight gain and adiposity and produced marked insulin resistance. Surprisingly liver-specific 11β-HSD1 knockout (LKO) mice given 11-DHC did not show any of the adverse metabolic effects seen in wild-type mice. This occurred despite the 11-DHC administration resulting in elevated circulating corticosterone, presumably from adipose tissue. Mice with global deletion of 11β-HSD1 (global knockout) were unaffected by treatment with 11-DHC, having no increase in circulating corticosterone and exhibiting no signs of metabolic impairment. Taken together, these data show that in the absence of 11β-HSD1 in the liver, mice are protected from the metabolic effects of 11-DHC administration, even though circulating glucocorticoids are increased. This implies that liver-derived intratissue glucocorticoids, rather than circulating glucocorticoids, contribute significantly to the development of metabolic syndrome and suggest that local action within hepatic tissue mediates these effects.
authors.affiliation: Faculty of Life Sciences, AV Hill Building, University of Manchester, Manchester, M13 9PT, United Kingdom. awhite@manchester.ac.uk.
authors.forename: Erika
authors.initials: E
authors.lastname: Harno
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Cottrell
authors.forename: Brian G
authors.initials: BG
authors.lastname: Keevil
authors.forename: Joanne
authors.initials: J
authors.lastname: DeSchoolmeester
authors.forename: Mohammad
authors.initials: M
authors.lastname: Bohlooly-Y
authors.forename: Harriet
authors.initials: H
authors.lastname: Andersén
authors.forename: Andrew V
authors.initials: AV
authors.lastname: Turnbull
authors.forename: Brendan
authors.initials: B
authors.lastname: Leighton
authors.forename: Anne
authors.initials: A
authors.lastname: White
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D050154:Adiposity; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D003345:Corticosterone / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism; D015536:Down-Regulation; D005938:Glucocorticoids / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000378:metabolism*; D006946:Hyperinsulinism / Q000209:etiology; D006963:Hyperphagia / Q000209:etiology / Q000503:physiopathology; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism / Q000503:physiopathology; D007333:Insulin Resistance; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D024821:Metabolic Syndrome / Q000097:blood / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010913:Pituitary-Adrenal System / Q000378:metabolism / Q000503:physiopathology; D015430:Weight Gain
chemical_list: D015415:Biomarkers; D005938:Glucocorticoids; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; C003552:11-dehydrocorticosterone; D003345:Corticosterone