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Female mice with transgenic disruption of 5-reductase 1 (5R1-KO) were studied, representing a “low androgen” state. Glucocorticoid clearance and stress responses were studied in mice aged 6m. Metabolism was assessed in mice on normal chow (aged 6 and 12m) and also in a separate cohort following 1m high-fat diet (aged 3m).
Female 5R1-KO mice had adrenal suppression (44% lower AUC corticosterone following stress), and upon corticosterone infusion accumulated hepatic glucocorticoids (~27% increased corticosterone). Female 5R1-KO mice aged 6m 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 12m. Hepatic transcript profiles supported impaired lipid -oxidation and increased triglyceride storage. Female 5R1-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, following disruption of 5R1 suggests phenotypic changes may be underpinned by altered metabolism of glucocorticoids rather than androgens.
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- 2 Finished
1/09/08 → 31/08/12
Andrew, R., Paterson, J. & Walker, B.
1/01/04 → 31/12/06