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Doig, C.L. 
ORCID: 0000-0001-9694-4230, Fletcher, R.S., Morgan, S.A., McCabe, E.L., Larner, D.P., Tomlinson, J.W., Stewart, P.M., Philp, A. and Lavery, G.G.,
2017.
11β-HSD1 modulates the set point of brown adipose tissue response to glucocorticoids in male mice.
Endocrinology, 158 (6), pp. 1964-1976.
ISSN 0013-7227
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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.
| Item Type: | Journal article | ||||||
|---|---|---|---|---|---|---|---|
| Publication Title: | Endocrinology | ||||||
| Creators: | Doig, C.L., Fletcher, R.S., Morgan, S.A., McCabe, E.L., Larner, D.P., Tomlinson, J.W., Stewart, P.M., Philp, A. and Lavery, G.G. | ||||||
| Publisher: | The Endocrine Society | ||||||
| Date: | 1 June 2017 | ||||||
| Volume: | 158 | ||||||
| Number: | 6 | ||||||
| ISSN: | 0013-7227 | ||||||
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| Divisions: | Schools > School of Science and Technology | ||||||
| Record created by: | Jonathan Gallacher | ||||||
| Date Added: | 11 Nov 2019 11:55 | ||||||
| Last Modified: | 18 Dec 2019 09:20 | ||||||
| URI: | https://irep.ntu.ac.uk/id/eprint/38199 |
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