5alpha-Reductase 1 (5aR1) catalyses A-ring reduction of glucocorticoids and androgens. We previously demonstrated that transgenic disruption of 5aR1 predisposes male mice to fatty liver and insulin resistance when challenged with a high-fat diet. Here, we have dissected the contributions of androgens and glucocorticoids to the metabolic phenotype using 2 models of enzyme inhibition (trangenesis and pharmacology).
Female 5aR1−/− mice (KO) and wild-type controls (WT) fed a chow diet were studied at 1 y. Obese Zucker rats (age 10 weeks) were studied intact (by oral glucose tolerance tests (GTT); 2 mg/g) and also at the same age, 4 weeks after gonadectomy (GDX) or sham surgery. Rats received either finasteride (0.35 mg/kg per day, 4 weeks; inhibits both rat 5aRs) or vehicle (5% ethanol). At cull, tissues were weighed and biochemical indices of insulin resistance assessed. Data are mean±S.E.M.: *P<0.05.
Female KO mice were heavier (32.3±1.14* vs 28.9±0.98 g), had greater adipose mass (omental: 31±3* vs 21±2 mg; mesenteric: 422±61* vs 257±44 mg; gonadal: 1150±189* vs 649±133 mg; sub-cutaneous: 429±56* vs 290±37 mg) and increased fed insulin (0.66±0.11* vs 0.28±0.06 ng/ml) compared to WT mice. Liver triglycerides (11.91±0.9* vs 9.08±0.54 nmol/mg) were also increased in KO mice.
Inhibition of 5aRs pharmacologically in obese Zucker rats did not alter weight gain, but induced insulin resistance (increased AUC for insulin following GTT; 2.76±0.3 vs 2.20±0.2 (ng/ml)*min) and also induced fatty liver (liver triglycerides; 10.55±1.12 vs 6.61±0.94 nmol/mg*). This increase in liver triglycerides induced by finasteride was also observed following GDX (increase 20%* sham, 26%* GDX).
In summary, the predisposition to steatosis and glucose intolerance due to lack of 5aR1 is more marked in female mice than males, and persists in rats following gonadectomy, supporting a key role for glucocorticoids as opposed to androgens in underpinning the phenotype. Furthermore treatment of men with benign prostatic hyperplasia with dual inhibitors of 5aRs may increase susceptibility to the metabolic syndrome.