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

5-Reductases irreversibly catalyse A-ring reduction of pregnene steroids, including glucocorticoids and androgens. Genetic disruption of 5-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-reductase 1 (5R1-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 5R1-KO mice had adrenal suppression (44% lower AUC corticosterone following stress), and upon corticosterone infusion accumulated hepatic glucocorticoids (~27% increased corticosterone). Female 5R1-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 5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, following disruption of 5R1 suggests phenotypic changes may be underpinned by altered metabolism of glucocorticoids rather than androgens.