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 Kenyon; Patrick W F Hadoke; Alex Odermatt; John A Keen; Brian R Walker

doi:10.1038/s41598-017-10410-1

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 journal › Article (Academic Journal) › peer-review

19 Citations (Scopus)

351 Downloads (Pure)

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 language	English
Article number	10633
Number of pages	11
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/s41598-017-10410-1
Publication status	Published - 6 Sept 2017

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41598-017-10410-1

Full-text PDF (final published version)
This is the final published version of the article (version of record). It first appeared online via Springer Nature at https://www.nature.com/articles/s41598-017-10410-1 . Please refer to any applicable terms of use of the publisher.
Final published version, 1.9 MBLicence: CC BY
Supplementary information PDF
This is the final published version of the article (version of record). It first appeared online via Springer Nature at https://www.nature.com/articles/s41598-017-10410-1 . Please refer to any applicable terms of use of the publisher.
Final published version, 608 KBLicence: CC BY

Handle.net

Persistent link

Cite this

Morgan, R. A., Beck, K. R., Nixon, M., Homer, N. Z. M., Crawford, A. A., Melchers, D., Houtman, R., Meijer, O. C., Stomby, A., Anderson, A. J., Upreti, R., Stimson, R. H., Olsson, T., Michoel, T., Cohain, A., Ruusalepp, A., Schadt, E. E., Björkegren, J. L. M., Andrew, R., ... Walker, B. R. (2017). Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity. Scientific Reports, 7, Article 10633. https://doi.org/10.1038/s41598-017-10410-1

@article{1231af0fcb9a4a0bbe40e56ce1f4b697,

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

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.",

author = "Morgan, {Ruth A} and Beck, {Katharina R} and Mark Nixon and Homer, {Natalie Z M} and Crawford, {Andrew A} and Diana Melchers and Ren{\'e} Houtman and Meijer, {Onno C} and Andreas Stomby and Anderson, {Anna J} and Rita Upreti and Stimson, {Roland H} and Tommy Olsson and Tom Michoel and Ariella Cohain and Arno Ruusalepp and Schadt, {Eric E} and Bj{\"o}rkegren, {Johan L M} and Ruth Andrew and Kenyon, {Christopher J} and Hadoke, {Patrick W F} and Alex Odermatt and Keen, {John A} and Walker, {Brian R}",

year = "2017",

month = sep,

day = "6",

doi = "10.1038/s41598-017-10410-1",

language = "English",

volume = "7",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Springer Nature",

}

Morgan, RA, Beck, KR, Nixon, M, Homer, NZM, Crawford, AA, Melchers, D, Houtman, R, Meijer, OC, Stomby, A, Anderson, AJ, Upreti, R, Stimson, RH, Olsson, T, Michoel, T, Cohain, A, Ruusalepp, A, Schadt, EE, Björkegren, JLM, Andrew, R, Kenyon, CJ, Hadoke, PWF, Odermatt, A, Keen, JA & Walker, BR 2017, 'Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity', Scientific Reports, vol. 7, 10633. https://doi.org/10.1038/s41598-017-10410-1

TY - JOUR

T1 - Carbonyl reductase 1 catalyzes 20β-reduction of glucocorticoids, modulating receptor activation and metabolic complications of obesity

AU - Morgan, Ruth A

AU - Beck, Katharina R

AU - Nixon, Mark

AU - Homer, Natalie Z M

AU - Crawford, Andrew A

AU - Melchers, Diana

AU - Houtman, René

AU - Meijer, Onno C

AU - Stomby, Andreas

AU - Anderson, Anna J

AU - Upreti, Rita

AU - Stimson, Roland H

AU - Olsson, Tommy

AU - Michoel, Tom

AU - Cohain, Ariella

AU - Ruusalepp, Arno

AU - Schadt, Eric E

AU - Björkegren, Johan L M

AU - Andrew, Ruth

AU - Kenyon, Christopher J

AU - Hadoke, Patrick W F

AU - Odermatt, Alex

AU - Keen, John A

AU - Walker, Brian R

PY - 2017/9/6

Y1 - 2017/9/6

N2 - 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.

AB - 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.

U2 - 10.1038/s41598-017-10410-1

DO - 10.1038/s41598-017-10410-1

M3 - Article (Academic Journal)

C2 - 28878267

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

M1 - 10633

ER -

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

Abstract

UN SDGs

Access to Document

Handle.net

Fingerprint

Cite this