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

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Abstract / Description of output

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
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-10410-1
Publication status	Published - 6 Sept 2017

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Journal Article

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10.1038/s41598-017-10410-1

s41598-017-10410-1Final published version, 1.9 MBLicence: Creative Commons: Attribution (CC-BY)

https://www.nature.com/articles/s41598-017-10410-1

John Keen
- John.Keened.acuk
- Royal (Dick) School of Veterinary Studies - Personal Chair of Equine Cardiovascular Medicine
Person: Academic: Research Active
Mark Nixon
- M.Nixoned.acuk
- Deanery of Clinical Sciences - Research Fellow
- Centre for Cardiovascular Science - Postdoctoral Researcher
Person: Academic: Research Active

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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(1), Article 10633. https://doi.org/10.1038/s41598-017-10410-1

@article{a63331d0ca0e449a8f5e0a515dabbb60,

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.",

keywords = "Journal Article",

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.}",

note = "Author contributions: RM, KB, MN, AC, DM, RH, AS, AA, RU, PH, TM, CK, JK and AO designed and/or conducted the experiments and/or analysed the data. NH and RA developed and supervised the mass spectrometry measurements. RS, TO, OM, and RA contributed to the design and execution of the clinical studies. AC, AR, ES and JB contributed data for GWAS analysis. RM and BW conceived the studies and supervised the experimental design, execution, and analysis. RM and BW wrote the manuscript, which was reviewed by all authors. Competing interests: All authors declare that they have no competing interests. ",

year = "2017",

month = sep,

day = "6",

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

language = "English",

volume = "7",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

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, no. 1, 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.

N1 - Author contributions: RM, KB, MN, AC, DM, RH, AS, AA, RU, PH, TM, CK, JK and AO designed and/or conducted the experiments and/or analysed the data. NH and RA developed and supervised the mass spectrometry measurements. RS, TO, OM, and RA contributed to the design and execution of the clinical studies. AC, AR, ES and JB contributed data for GWAS analysis. RM and BW conceived the studies and supervised the experimental design, execution, and analysis. RM and BW wrote the manuscript, which was reviewed by all authors. Competing interests: All authors declare that they have no competing interests.

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.

KW - Journal Article

U2 - 10.1038/s41598-017-10410-1

DO - 10.1038/s41598-017-10410-1

M3 - Article

C2 - 28878267

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 10633

ER -

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

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John Keen

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