Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity

Ruth A Morgan, Katharina R Beck, Mark Nixon, Natalie Z M Homer, Andrew A Crawford, Diana Melchers, René Houtman, Onno C Meijer, Andreas Stomby, Anna J Anderson, Rita Upreti, Roland H Stimson, Tommy Olsson, Tom Michoel, Ariella Cohain, Arno Ruusalepp, Eric E Schadt, Johan L M Björkegren, Ruth Andrew, Christopher J KenyonPatrick W F Hadoke, Alex Odermatt, John A Keen, Brian R Walker

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Carbonyl Reductase 1 (CBR1) is a ubiquitously expressed cytosolic enzyme important in exogenous drug metabolism but the physiological function of which is unknown. Here, we describe a role for CBR1 in metabolism of glucocorticoids. CBR1 catalyzes the NADPH- dependent production of 20β-dihydrocortisol (20β-DHF) from cortisol. CBR1 provides the major route of cortisol metabolism in horses and is up-regulated in adipose tissue in obesity in horses, humans and mice. We demonstrate that 20β-DHF is a weak endogenous agonist of the human glucocorticoid receptor (GR). Pharmacological inhibition of CBR1 in diet-induced obesity in mice results in more marked glucose intolerance with evidence for enhanced hepatic GR signaling. These findings suggest that CBR1 generating 20β-dihydrocortisol is a novel pathway modulating GR activation and providing enzymatic protection against excessive GR activation in obesity.

Original languageEnglish
Article number10633
Number of pages11
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 6 Sep 2017

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