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

Research output: Contribution to journalArticlepeer-review

Authors

  • Stuart Morgan
  • Emma McCabe
  • Jeremy Tomlinson
  • Paul Stewart

External organisations

  • University of Oxford
  • University of Leeds

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.

Details

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

Keywords

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