11β-HSD1 modulates the set-point of brown adipose tissue response to glucocorticoids in male mice

Craig Doig, Rachel Fletcher, Stuart Morgan, Emma McCabe, Dean Larner, Jeremy Tomlinson, Paul Stewart, Andrew Philp, Gareth Lavery

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)
139 Downloads (Pure)

Abstract

Glucocorticoids are potent regulators of energy metabolism. Chronic glucocorticoid exposure supresses brown adipose tissue (BAT) thermogenic capacity in mice, with evidence for a similar effect in humans. Intracellular glucocorticoid levels are regulated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity which can amplify circulating glucocorticoid concentrations. Therefore, 11β-HSD1 could modulate the impact of glucocorticoids on BAT function. Here we investigate how 11β-HSD1 regulates the molecular architecture of BAT in the context of glucocorticoid excess and aging. Circulating glucocorticoid excess was induced in 11β-HSD1 knockout (KO) and WT mice by supplementing drinking water with 100μg/ml corticosterone, and the effects on molecular markers of BAT function and mitochondrial activity 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-HSD1KO mice to model lifetime glucocorticoid exposure. BAT 11β-HSD1 expression and activity is elevated in response to glucocorticoid excess and with aging. 11β-HSD1KO BAT resists the suppression of UCP1 and mitochondrial respiratory chain subunit proteins normally imposed by glucocorticoid excess. Furthermore, brown adipocytes from 11β-HSD1KO mice have elevated basal mitochondrial function, and are able to resist glucocorticoid mediated repression of activity. BAT from aged 11β-HSD1KO mice show elevated UCP1 protein, mitochondrial content and a favourable profile of BAT function. These data reveal a novel mechanism in which increased 11β-HSD1 expression, in the context of glucocorticoid excess and aging, impairs the molecular and metabolic function of BAT.

Original languageEnglish
Pages (from-to)1964-1976
JournalEndocrinology
Volume158
Issue number6
Early online date27 Mar 2017
DOIs
Publication statusPublished - 1 Jun 2017

Keywords

  • aging
  • Mitochondria
  • Glucocorticoids
  • Adipocytes
  • brown fat
  • Glasgow Coma Scale
  • mice

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