11β-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess

Stuart A Morgan, Emma L McCabe, Laura L Gathercole, Zaki K Hassan-Smith, Dean P Larner, Iwona J Bujalska, Paul M Stewart, Jeremy W Tomlinson, Gareth G Lavery

Research output: Contribution to journalArticlepeer-review

147 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E2482-91
JournalNational Academy of Sciences. Proceedings
Volume111
Issue number24
Early online date2 Jun 2014
DOIs
Publication statusPublished - 17 Jun 2014

Keywords

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1
  • Adipose Tissue
  • Animals
  • Anti-Inflammatory Agents
  • Blood Pressure
  • Cushing Syndrome
  • Disease Models, Animal
  • Fatty Acids, Nonesterified
  • Gene Expression Regulation
  • Glucocorticoids
  • Glucose Intolerance
  • Glucose Tolerance Test
  • Hydrocortisone
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Regeneration
  • Triglycerides

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