title: 11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess.
abstract: The adverse metabolic effects of prescribed and endogenous glucocorticoid (GC) excess, Cushing syndrome, create a significant health burden. We found that tissue regeneration of GCs by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), rather than circulating delivery, is critical to developing the phenotype of GC excess; 11β-HSD1 KO mice with circulating GC excess are protected from the glucose intolerance, hyperinsulinemia, hepatic steatosis, adiposity, hypertension, myopathy, and dermal atrophy of Cushing syndrome. Whereas liver-specific 11β-HSD1 KO mice developed a full Cushingoid phenotype, adipose-specific 11β-HSD1 KO mice were protected from hepatic steatosis and circulating fatty acid excess. These data challenge our current view of GC action, demonstrating 11β-HSD1, particularly in adipose tissue, is key to the development of the adverse metabolic profile associated with circulating GC excess, offering 11β-HSD1 inhibition as a previously unidentified approach to treat Cushing syndrome.
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Morgan
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Emma L
authors.initials: EL
authors.lastname: McCabe
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Laura L
authors.initials: LL
authors.lastname: Gathercole
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Zaki K
authors.initials: ZK
authors.lastname: Hassan-Smith
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Larner
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Iwona J
authors.initials: IJ
authors.lastname: Bujalska
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; andSchool of Medicine, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Stewart
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; and j.w.tomlinson@bham.ac.uk.
authors.forename: Jeremy W
authors.initials: JW
authors.lastname: Tomlinson
authors.affiliation: Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, Institute of Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom; and.
authors.forename: Gareth G
authors.initials: GG
authors.lastname: Lavery
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D001794:Blood Pressure; D003480:Cushing Syndrome / Q000097:blood* / Q000235:genetics*; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000097:blood*; D018149:Glucose Intolerance; D005951:Glucose Tolerance Test; D006854:Hydrocortisone / Q000097:blood*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012038:Regeneration / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: D000893:Anti-Inflammatory Agents; D005230:Fatty Acids, Nonesterified; D005938:Glucocorticoids; D014280:Triglycerides; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone
keywords: HSD11b1; cortisol; endocrinology; hypercortisolemia; steroids