title: 11β-HSD1 Modulates the Set Point of Brown Adipose Tissue Response to Glucocorticoids in Male Mice.
abstract: Glucocorticoids (GCs) are potent regulators of energy metabolism. Chronic GC exposure suppresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular GC levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, which can amplify circulating GC concentrations. Therefore, 11β-HSD1 could modulate the impact of GCs on BAT function. This study investigated how 11β-HSD1 regulates the molecular architecture of BAT in the context of GC excess and aging. Circulating GC excess was induced in 11β-HSD1 knockout (KO) and wild-type mice by supplementing drinking water with 100 μg/mL corticosterone, and the effects on molecular markers of BAT function and mitochondrial activity were assessed. Brown adipocyte primary cultures were used to examine cell autonomous consequences of 11β-HSD1 deficiency. Molecular markers of BAT function were also examined in aged 11β-HSD1 KO mice to model lifetime GC exposure. BAT 11β-HSD1 expression and activity were elevated in response to GC excess and with aging. 11β-HSD1 KO BAT resisted the suppression of uncoupling protein 1 (UCP1) and mitochondrial respiratory chain subunit proteins normally imposed by GC excess. Furthermore, brown adipocytes from 11β-HSD1 KO mice had elevated basal mitochondrial function and were able to resist GC-mediated repression of activity. BAT from aged 11β-HSD1 KO mice showed elevated UCP1 protein and mitochondrial content, and a favorable profile of BAT function. These data reveal a novel mechanism in which increased 11β-HSD1 expression, in the context of GC excess and aging, impairs the molecular and metabolic function of BAT.
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Doig
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Fletcher
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Morgan
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.
authors.forename: Emma L
authors.initials: EL
authors.lastname: McCabe
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Larner
authors.affiliation: Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LE, United Kingdom.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
authors.affiliation: Faculty of Medicine and Health, University of Leeds, Leeds LS2 9NL, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.affiliation: School of Sport Exercise and Rehabilitation Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
authors.forename: Andrew
authors.initials: A
authors.lastname: Philp
authors.affiliation: Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.|Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham B15 2TH, United Kingdom.
authors.forename: Gareth G
authors.initials: GG
authors.lastname: Lavery
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000502:physiology*; D002001:Adipose Tissue, Brown / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D000071256:Uncoupling Protein 1 / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1