11β-HSD1 Modulates the Set Point of Brown Adipose Tissue Response to Glucocorticoids in Male Mice

Endocrinology. 2017 Jun 1;158(6):1964-1976. doi: 10.1210/en.2016-1722.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / physiology*
  • Adipose Tissue, Brown / drug effects*
  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Cells, Cultured
  • Gene Expression Regulation, Enzymologic / drug effects
  • Glucocorticoids / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Uncoupling Protein 1 / metabolism

Substances

  • Glucocorticoids
  • Ucp1 protein, mouse
  • Uncoupling Protein 1
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1