Carbonyl reductase 1 amplifies glucocorticoid action in adipose tissue and impairs glucose tolerance in lean mice
| Autor: | Mark Nixon, Emma Allan, René Houtman, Matthew G.F. Sharp, Onno C. Meijer, Lee Murphy, Allende Miguelez-Crespo, Audrey Coutts, Alex Odermatt, Angie Fawkes, Scott G. Denham, Brian R. Walker, Katharina Beck, Elisa Villalobos, Natalie Z.M. Homer, Ruth Morgan, Patricia Lee, Martha V. Koerner, Rachel M.B. Bell |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male Mineralocorticoid receptor Adipose tissue Glucocorticoid receptor chemistry.chemical_compound Mice 0302 clinical medicine Glucocorticoid Corticosterone glucocorticoid receptor Glucose homeostasis Homeostasis glucose Receptor Internal medicine non-esterified fatty acids: GTT glucose tolerance test Tk thymidine kinase UTR untranslated region Adipose Tissue SNPs single nucleotide polymorphisms Gene Knockdown Techniques 20β-DHB/F 20β-dihydrocorticosterone/dihydrocortisol qPCR quantitative polymerase chain reaction Original Article Female medicine.drug Signal Transduction medicine.medical_specialty CBR1 DEGs differentially expressed genes 030209 endocrinology & metabolism Mice Transgenic Diet High-Fat 03 medical and health sciences Receptors Glucocorticoid Glucose Intolerance medicine Animals Humans NeoR neomycin resistant: RMCE Obesity Molecular Biology recombination-mediated cassette exchange NEFA Glucocorticoids ITT insulin tolerance test ELISA enzyme-linked immunoassay mineralocorticoid receptor GR glucocorticoid receptor business.industry 11β-HSD1/2 11β-hydroxysteroid dehydrogenase type 1/2 corticosterone LC-MS/MS liquid chromatography tandem mass spectrometry Cbr1 carbonyl reductase 1 Cell Biology MR mineralocorticoid receptor PuroR puromycin resistance RC31-1245 Mice Inbred C57BL Alcohol Oxidoreductases Disease Models Animal 030104 developmental biology Endocrinology HEK293 Cells Receptors Mineralocorticoid Metabolism Glucose chemistry glucocorticoid business metabolism |
| Zdroj: | 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 Molecular Metabolism MOLECULAR METABOLISM, 48. ELSEVIER MOLECULAR METABOLISM Molecular Metabolism, Vol 48, Iss, Pp 101225-(2021) |
| Popis: | 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. Highlights • Carbonyl reductase 1 (Cbr1) is a novel regulator of adipose glucocorticoid metabolism and glucose homeostasis. • Cbr1 metabolises corticosterone to 20β-dihydrocorticosterone, which is both a glucocorticoid and mineralocorticoid receptor agonist. • Global knockdown of Cbr1 improves glucose tolerance in lean male mice. • Overexpression of Cbr1 in adipose tissue worsens glucose tolerance in lean male and female mice. |
| Databáze: | OpenAIRE |
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