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Metabolic dysfunction in female mice with disruption of 5α-reductase 1

5α-Reductases irreversibly catalyse A-ring reduction of pregnene steroids, including glucocorticoids and androgens. Genetic disruption of 5α-reductase 1 in male mice impairs glucocorticoid clearance and predisposes to glucose intolerance and hepatic steatosis upon metabolic challenge. However, it is...

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Autores principales: Livingstone, Dawn E W, Di Rollo, Emma M, Mak, Tracy C-S, Sooy, Karen, Walker, Brian R, Andrew, Ruth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Bioscientifica Ltd 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118938/
https://www.ncbi.nlm.nih.gov/pubmed/27647861
http://dx.doi.org/10.1530/JOE-16-0125
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author Livingstone, Dawn E W
Di Rollo, Emma M
Mak, Tracy C-S
Sooy, Karen
Walker, Brian R
Andrew, Ruth
author_facet Livingstone, Dawn E W
Di Rollo, Emma M
Mak, Tracy C-S
Sooy, Karen
Walker, Brian R
Andrew, Ruth
author_sort Livingstone, Dawn E W
collection PubMed
description 5α-Reductases irreversibly catalyse A-ring reduction of pregnene steroids, including glucocorticoids and androgens. Genetic disruption of 5α-reductase 1 in male mice impairs glucocorticoid clearance and predisposes to glucose intolerance and hepatic steatosis upon metabolic challenge. However, it is unclear whether this is driven by changes in androgen and/or glucocorticoid action. Female mice with transgenic disruption of 5α-reductase 1 (5αR1-KO) were studied, representing a ‘low androgen’ state. Glucocorticoid clearance and stress responses were studied in mice aged 6 months. Metabolism was assessed in mice on normal chow (aged 6 and 12 m) and also in a separate cohort following 1-month high-fat diet (aged 3 m). Female 5αR1-KO mice had adrenal suppression (44% lower AUC corticosterone after stress), and upon corticosterone infusion, accumulated hepatic glucocorticoids (~27% increased corticosterone). Female 5αR1-KO mice aged 6 m fed normal chow demonstrated insulin resistance (~35% increased area under curve (AUC) for insulin upon glucose tolerance testing) and hepatic steatosis (~33% increased hepatic triglycerides) compared with controls. This progressed to obesity (~12% increased body weight) and sustained insulin resistance (~38% increased AUC insulin) by age 12 m. Hepatic transcript profiles supported impaired lipid β-oxidation and increased triglyceride storage. Female 5αR1-KO mice were also predisposed to develop high-fat diet-induced insulin resistance. Exaggerated predisposition to metabolic disorders in female mice, compared with that seen in male mice, after disruption of 5αR1 suggests phenotypic changes may be underpinned by altered metabolism of glucocorticoids rather than androgens.
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spelling pubmed-51189382016-12-19 Metabolic dysfunction in female mice with disruption of 5α-reductase 1 Livingstone, Dawn E W Di Rollo, Emma M Mak, Tracy C-S Sooy, Karen Walker, Brian R Andrew, Ruth J Endocrinol Research 5α-Reductases irreversibly catalyse A-ring reduction of pregnene steroids, including glucocorticoids and androgens. Genetic disruption of 5α-reductase 1 in male mice impairs glucocorticoid clearance and predisposes to glucose intolerance and hepatic steatosis upon metabolic challenge. However, it is unclear whether this is driven by changes in androgen and/or glucocorticoid action. Female mice with transgenic disruption of 5α-reductase 1 (5αR1-KO) were studied, representing a ‘low androgen’ state. Glucocorticoid clearance and stress responses were studied in mice aged 6 months. Metabolism was assessed in mice on normal chow (aged 6 and 12 m) and also in a separate cohort following 1-month high-fat diet (aged 3 m). Female 5αR1-KO mice had adrenal suppression (44% lower AUC corticosterone after stress), and upon corticosterone infusion, accumulated hepatic glucocorticoids (~27% increased corticosterone). Female 5αR1-KO mice aged 6 m fed normal chow demonstrated insulin resistance (~35% increased area under curve (AUC) for insulin upon glucose tolerance testing) and hepatic steatosis (~33% increased hepatic triglycerides) compared with controls. This progressed to obesity (~12% increased body weight) and sustained insulin resistance (~38% increased AUC insulin) by age 12 m. Hepatic transcript profiles supported impaired lipid β-oxidation and increased triglyceride storage. Female 5αR1-KO mice were also predisposed to develop high-fat diet-induced insulin resistance. Exaggerated predisposition to metabolic disorders in female mice, compared with that seen in male mice, after disruption of 5αR1 suggests phenotypic changes may be underpinned by altered metabolism of glucocorticoids rather than androgens. Bioscientifica Ltd 2016-11-11 /pmc/articles/PMC5118938/ /pubmed/27647861 http://dx.doi.org/10.1530/JOE-16-0125 Text en © 2017 The authors http://creativecommons.org/licenses/by/3.0/ This work is licensed under a Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/licenses/by/3.0/) .
spellingShingle Research
Livingstone, Dawn E W
Di Rollo, Emma M
Mak, Tracy C-S
Sooy, Karen
Walker, Brian R
Andrew, Ruth
Metabolic dysfunction in female mice with disruption of 5α-reductase 1
title Metabolic dysfunction in female mice with disruption of 5α-reductase 1
title_full Metabolic dysfunction in female mice with disruption of 5α-reductase 1
title_fullStr Metabolic dysfunction in female mice with disruption of 5α-reductase 1
title_full_unstemmed Metabolic dysfunction in female mice with disruption of 5α-reductase 1
title_short Metabolic dysfunction in female mice with disruption of 5α-reductase 1
title_sort metabolic dysfunction in female mice with disruption of 5α-reductase 1
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5118938/
https://www.ncbi.nlm.nih.gov/pubmed/27647861
http://dx.doi.org/10.1530/JOE-16-0125
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