11β-HSD1 Modulates the Set Point of Brown Adipose Tissue Response to Glucocorticoids in Male Mice.
Doig CL., Fletcher RS., Morgan SA., McCabe EL., Larner DP., Tomlinson JW., Stewart PM., Philp A., Lavery GG.
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.