Journal
JOURNAL OF ENDOCRINOLOGY
Volume 232, Issue 1, Pages 29-36Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/JOE-16-0125
Keywords
glucocorticoid; steroid metabolising hormones; metabolism; obesity
Categories
Funding
- Wellcome Trust [072217/7/03/Z]
- British Heart Foundation [FS/08/063, FS/08/065]
- Carnegie Trust
- British Heart Foundation [RG/11/4/28734] Funding Source: researchfish
- Chief Scientist Office [CZB/4/642] Funding Source: researchfish
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5 alpha-Reductases irreversibly catalyse A-ring reduction of pregnene steroids, including glucocorticoids and androgens. Genetic disruption of 5 alpha-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 5 alpha-reductase 1 (5 alpha R1-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 5 alpha R1-K0 mice had adrenal suppression (44% lower AUC corticosterone after stress), and upon corticosterone infusion, accumulated hepatic glucocorticoids (similar to 27% increased corticosterone). Female 5 alpha R1-KO mice aged 6 m fed normal chow demonstrated insulin resistance (similar to 35% increased area under curve (AUC) for insulin upon glucose tolerance testing) and hepatic steatosis (similar to 33% increased hepatic triglycerides) compared with controls. This progressed to obesity (similar to 12% increased body weight) and sustained insulin resistance (similar to 38% increased AUC insulin) by age 12 m. Hepatic transcript profiles supported impaired lipid beta-oxidation and increased triglyceride storage. Female 5 alpha R1-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 5 alpha R1 suggests phenotypic changes may be underpinned by altered metabolism of glucocorticoids rather than androgens.
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