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

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.

The glucocorticoid receptor in brown adipocytes is dispensable for control of energy homeostasis

“…GCs have been hypothesized to exert the majority of their tissuespecific actions based on the local activity of the enzyme 11b-HSD1, which converts inactive 11-dehydrocorticosterone to the active corticosterone in rodents, or cortisol in humans [21]. Corticosterone excess caused by administration via the drinking water suppresses the induction of UCP1 in the BAT of control mice, while in wholebody 11b-HSD1 knockout mice, UCP1 levels were not elevated in response to the corticosterone treatment [22]. Moreover, primary brown adipocytes from these knockout mice showed elevated mitochondrial function, and aged 11b-HSD1 knockout mice displayed improved BAT function compared to controls.…”

Glucocorticoid Receptor and Adipocyte Biology

“…Moreover, adrenalectomy and GR antagonist increased the expression of Ucp1 and elevates BAT thermogenesis [ 28 , 95 , 96 ]. Similarly, mice lacking 11β-hydroxysteroid dehydrogenase type 1 ( 11β-HSD1 −/− ) were protected by suppression of BAT activity by exogenous glucocorticoids [ 97 ]. Although the expression of Ucp1 was similar between corticosterone treated wild type and 11β-HSD1 −/− mice, several genes encoding proteins in the activation of thermogenesis and mitochondrial respiration were expressed in lower levels in 11β-HSD1 −/− mice [ 97 ].…”

“…Similarly, mice lacking 11β-hydroxysteroid dehydrogenase type 1 ( 11β-HSD1 −/− ) were protected by suppression of BAT activity by exogenous glucocorticoids [ 97 ]. Although the expression of Ucp1 was similar between corticosterone treated wild type and 11β-HSD1 −/− mice, several genes encoding proteins in the activation of thermogenesis and mitochondrial respiration were expressed in lower levels in 11β-HSD1 −/− mice [ 97 ]. Treating primary brown adipocytes isolated from wild type mice with corticosterone reduced oxygen consumption and the expression of thermogenic genes, such as Ucp1, and brown/beige makers Cox8b and Cox7a1, which encodes proteins involved in mitochondrial oxidative phosphorylation [ 97 ].…”

“…Although the expression of Ucp1 was similar between corticosterone treated wild type and 11β-HSD1 −/− mice, several genes encoding proteins in the activation of thermogenesis and mitochondrial respiration were expressed in lower levels in 11β-HSD1 −/− mice [ 97 ]. Treating primary brown adipocytes isolated from wild type mice with corticosterone reduced oxygen consumption and the expression of thermogenic genes, such as Ucp1, and brown/beige makers Cox8b and Cox7a1, which encodes proteins involved in mitochondrial oxidative phosphorylation [ 97 ]. Interestingly, although corticosterone still suppressed the expression of thermogenic and mitochondrial genes in primary brown adipocytes isolated from 11β-HSD1 −/− mice, the basal expression of these genes was higher than those of wild type mice [ 97 ].…”

“…Treating primary brown adipocytes isolated from wild type mice with corticosterone reduced oxygen consumption and the expression of thermogenic genes, such as Ucp1, and brown/beige makers Cox8b and Cox7a1, which encodes proteins involved in mitochondrial oxidative phosphorylation [ 97 ]. Interestingly, although corticosterone still suppressed the expression of thermogenic and mitochondrial genes in primary brown adipocytes isolated from 11β-HSD1 −/− mice, the basal expression of these genes was higher than those of wild type mice [ 97 ]. Similarly, the oxygen consumption rate was also higher in primary brown adipocytes of 11β-HSD1 −/− mice [ 97 ].…”