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

R.A. Morgan; K.R. Beck; M. Nixon; N.Z.M. Homer; A.A. Crawford; D. Melchers; R. Houtman; O.C. Meijer; A. Stomby; A.J. Anderson; R. Upreti; R.H. Stimson; T. Olsson; T. Michoel; A. Cohain; A. Ruusalepp; E.E. Schadt; J.L.M. Björkegren; R. Andrew; C.J. Kenyon; P.W.F. Hadoke; A. Odermatt; J.A. Keen; B.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

R.A. Morgan, K.R. Beck, M. Nixon, N.Z.M. Homer, A.A. Crawford, D. Melchers, R. Houtman, O.C. Meijer, A. Stomby, A.J. Anderson, R. Upreti, R.H. Stimson, T. Olsson, T. Michoel, A. Cohain, A. Ruusalepp, E.E. Schadt, J.L.M. Björkegren, R. Andrew, C.J. KenyonP.W.F. Hadoke, A. Odermatt, J.A. Keen, B.R. Walker

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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 language	English
Article number	10633
Journal	Scientific Reports
Volume	7
DOIs	https://doi.org/10.1038/s41598-017-10410-1
Publication status	Print publication - 6 Sept 2017
Externally published	Yes

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

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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 = "R.A. Morgan and K.R. Beck and M. Nixon and N.Z.M. Homer and A.A. Crawford and D. Melchers and R. Houtman and O.C. Meijer and A. Stomby and A.J. Anderson and R. Upreti and R.H. Stimson and T. Olsson and T. Michoel and A. Cohain and A. Ruusalepp and E.E. Schadt and J.L.M. Bj{\"o}rkegren and R. Andrew and C.J. Kenyon and P.W.F. Hadoke and A. Odermatt and J.A. Keen and B.R. Walker",

year = "2017",

month = sep,

day = "6",

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

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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, R.A.

AU - Beck, K.R.

AU - Nixon, M.

AU - Homer, N.Z.M.

AU - Crawford, A.A.

AU - Melchers, D.

AU - Houtman, R.

AU - Meijer, O.C.

AU - Stomby, A.

AU - Anderson, A.J.

AU - Upreti, R.

AU - Stimson, R.H.

AU - Olsson, T.

AU - Michoel, T.

AU - Cohain, A.

AU - Ruusalepp, A.

AU - Schadt, E.E.

AU - Björkegren, J.L.M.

AU - Andrew, R.

AU - Kenyon, C.J.

AU - Hadoke, P.W.F.

AU - Odermatt, A.

AU - Keen, J.A.

AU - Walker, B.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.

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U2 - 10.1038/s41598-017-10410-1

DO - 10.1038/s41598-017-10410-1

M3 - Article

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

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