Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.

Rachel Bell; Elisa Villalobos; Mark Nixon; Allende  Miguelez-Crespo1; Lee Murphy; Angie Fawkes; Audrey Coutts; Matthew Gf Sharp; Martha Koerner; Emma Allan; Onno C.  Meijer; René  Houtman; Alex Odermatt; Katharina R Beck; Scott Denham; Patricia Lee; Natalie Homer; Brian R Walker; Ruth A Morgan

doi:10.1016/j.molmet.2021.101225

Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.

Rachel Bell, Elisa Villalobos, Mark Nixon, Allende Miguelez-Crespo1, Lee Murphy, Angie Fawkes, Audrey Coutts, Matthew Gf Sharp, Martha Koerner, Emma Allan, Onno C. Meijer, René Houtman , Alex Odermatt, Katharina R Beck, Scott Denham, Patricia Lee, Natalie Homer, Brian R Walker, Ruth A Morgan

Research output: Contribution to journal › Article › peer-review

Abstract

Objective
Carbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states.

Methods
The actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding.

Results
20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding.

Conclusions
Carbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.

Original language	English
Journal	Molecular Metabolism
Early online date	27 Mar 2021
DOIs	https://doi.org/10.1016/j.molmet.2021.101225
Publication status	E-pub ahead of print - 27 Mar 2021

Keywords

Obesity
glucocorticoid
metabolism
glucose
corticosterone
mineralocorticoid receptor
glucocorticoid receptor

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10.1016/j.molmet.2021.101225

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Bell, R., Villalobos, E., Nixon, M., Miguelez-Crespo1, A., Murphy, L., Fawkes, A., Coutts, A., Sharp, M. G., Koerner, M., Allan, E., Meijer, O. C., Houtman , R., Odermatt, A., Beck, K. R., Denham, S., Lee, P., Homer, N., Walker, B. R., & Morgan, R. A. (2021). Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice. Molecular Metabolism. https://doi.org/10.1016/j.molmet.2021.101225

@article{3f509c2f136744499d9a04846654fc10,

title = "Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.",

abstract = "ObjectiveCarbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states.MethodsThe actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding.Results20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding.ConclusionsCarbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.",

keywords = "Obesity, glucocorticoid, metabolism, glucose, corticosterone, mineralocorticoid receptor, glucocorticoid receptor",

author = "Rachel Bell and Elisa Villalobos and Mark Nixon and Allende Miguelez-Crespo1 and Lee Murphy and Angie Fawkes and Audrey Coutts and Sharp, {Matthew Gf} and Martha Koerner and Emma Allan and Meijer, {Onno C.} and Ren{\'e} Houtman and Alex Odermatt and Beck, {Katharina R} and Scott Denham and Patricia Lee and Natalie Homer and Walker, {Brian R} and Morgan, {Ruth A}",

year = "2021",

month = mar,

day = "27",

doi = "10.1016/j.molmet.2021.101225",

language = "English",

journal = "Molecular Metabolism",

issn = "2212-8778",

publisher = "Elsevier",

}

Bell, R, Villalobos, E, Nixon, M, Miguelez-Crespo1, A, Murphy, L , Fawkes, A, Coutts, A, Sharp, MG, Koerner, M, Allan, E, Meijer, OC, Houtman , R, Odermatt, A, Beck, KR, Denham, S, Lee, P, Homer, N, Walker, BR & Morgan, RA 2021, 'Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.', Molecular Metabolism. https://doi.org/10.1016/j.molmet.2021.101225

TY - JOUR

T1 - Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.

AU - Bell, Rachel

AU - Villalobos, Elisa

AU - Nixon, Mark

AU - Miguelez-Crespo1, Allende

AU - Murphy, Lee

AU - Fawkes, Angie

AU - Coutts, Audrey

AU - Sharp, Matthew Gf

AU - Koerner, Martha

AU - Allan, Emma

AU - Meijer, Onno C.

AU - Houtman , René

AU - Odermatt, Alex

AU - Beck, Katharina R

AU - Denham, Scott

AU - Lee, Patricia

AU - Homer, Natalie

AU - Walker, Brian R

AU - Morgan, Ruth A

PY - 2021/3/27

Y1 - 2021/3/27

N2 - ObjectiveCarbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states.MethodsThe actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding.Results20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding.ConclusionsCarbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.

AB - ObjectiveCarbonyl reductase 1 (Cbr1), a recently discovered contributor to tissue glucocorticoid metabolism converting corticosterone to 20β-dihydrocorticosterone (20β-DHB), is upregulated in adipose tissue of obese humans and mice and may contribute to cardiometabolic complications of obesity. This study tested the hypothesis that Cbr1-mediated glucocorticoid metabolism influences glucocorticoid and mineralocorticoid receptor activation in adipose tissue and impacts glucose homeostasis in lean and obese states.MethodsThe actions of 20β-DHB on corticosteroid receptors in adipose tissue were investigated first using a combination of in silico, in vitro, and transcriptomic techniques and then in vivo administration in combination with receptor antagonists. Mice lacking one Cbr1 allele and mice overexpressing Cbr1 in their adipose tissue underwent metabolic phenotyping before and after induction of obesity with high-fat feeding.Results20β-DHB activated both the glucocorticoid and mineralocorticoid receptor in adipose tissue and systemic administration to wild-type mice induced glucose intolerance, an effect that was ameliorated by both glucocorticoid and mineralocorticoid receptor antagonism. Cbr1 haploinsufficient lean male mice had lower fasting glucose and improved glucose tolerance compared with littermate controls, a difference that was abolished by administration of 20β-DHB and absent in female mice with higher baseline adipose 20β-DHB concentrations than male mice. Conversely, overexpression of Cbr1 in adipose tissue resulted in worsened glucose tolerance and higher fasting glucose in lean male and female mice. However, neither Cbr1 haploinsfficiency nor adipose overexpression affected glucose dyshomeostasis induced by high-fat feeding.ConclusionsCarbonyl reductase 1 is a novel regulator of glucocorticoid and mineralocorticoid receptor activation in adipose tissue that influences glucose homeostasis in lean mice.

KW - Obesity

KW - glucocorticoid

KW - metabolism

KW - glucose

KW - corticosterone

KW - mineralocorticoid receptor

KW - glucocorticoid receptor

U2 - 10.1016/j.molmet.2021.101225

DO - 10.1016/j.molmet.2021.101225

M3 - Article

JO - Molecular Metabolism

JF - Molecular Metabolism

SN - 2212-8778

ER -

Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice.

Abstract

Keywords

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