Endocrine Abstracts

Background: 5α-reductase 1 (5αR1) metabolises steroids such as glucocorticoids and androgens, and is highly expressed in murine liver. Genetic disruption of 5αR1 leads to adverse metabolic changes in mice. We hypothesised that dutasteride, a 5αR inhibitor, induces insulin resistance in mice, as in humans, and this effect is underpinned by increased hepatic glucocorticoid action; an experimental paradigm was set up using A-348441, a liver-selective glucocorticoid receptor (GR) antagonist, and then utilised to assessed the contribution of increased hepatic glucocorticoid action to the metabolic consequences of dutasteride.

Methods: C57BL6/J male mice (n=8–15/group; age 12 weeks) were given high fat (HF), HF with A-348441 (KaroBio), HF+dutasteride (Dut), or HF+Dut+A-348441 diet for 4 weeks. Glucose tolerance tests (GTT) were performed at week 3, with mice culled at week 4. Plasma insulin and corticosterone were measured by ELISA and plasma glucose spectrophotometrically. Data are mean±S.E.M., ^#P<0.05 vs HF diet and ^$P<0.05 vs HF+Dut diet.

Results: Plasma corticosterone concentrations were not changed by A-348441, supporting liver-selective GR antagonism. A-348441 improved metabolic health of mice receiving a HF diet, preventing HF-induced bodyweight gain (34.3±0.5 g vs 31±0.8 g^#), and total white adipose depot weight gain (2.46±0.1 g vs 1.58±0.1 g^#), and attenuating HF-induced elevations in fasting plasma insulin, fasting glucose and insulin response to GTT (lowered by 52^#, 25^#, and 44%^# respectively). Inhibition of 5αRs with dutasteride impaired insulin sensitivity, with increased insulin response to GTT but did not change body weight, total adipose depot weight, fasting insulin, fasting glucose, or glucose response to GTT; A-348441 reduced this hyperinsulinaemia (235.9±17 ng/ml per min vs 329.3±16^# ng/ml per min vs 198.4±25^$ ng/ml per min).

Conclusions: Liver-specific GR antagonism ameliorates the metabolic consequences of acute diet-induced obesity. Hyperinsulinaemia caused by inhibition of 5αRs was ameliorated by A-348441, suggesting that hepatic glucocorticoid action plays a substantial role in metabolic dysfunction caused by 5αR inhibition. Moreover, targeting hepatic GR may be beneficial in maintaining metabolic homeostasis in diet-induced obesity.