First Author | Mak TCS | Year | 2019 |
Journal | Endocrinology | Volume | 160 |
Issue | 9 | Pages | 2061-2073 |
PubMed ID | 31199473 | Mgi Jnum | J:278970 |
Mgi Id | MGI:6359981 | Doi | 10.1210/en.2019-00236 |
Citation | Mak TCS, et al. (2019) Role of Hepatic Glucocorticoid Receptor in Metabolism in Models of 5alphaR1 Deficiency in Male Mice. Endocrinology 160(9):2061-2073 |
abstractText | Inhibition of 5alpha-reductases impairs androgen and glucocorticoid metabolism and induces insulin resistance in humans and rodents. The contribution of hepatic glucocorticoids to these adverse metabolic changes was assessed using a liver-selective glucocorticoid receptor (GR) antagonist, A-348441. Mice lacking 5alpha-reductase 1 (5alphaR1-KO) and their littermate controls were studied during consumption of a high-fat diet, with or without A-348441(120 mg/kg/d). Male C57BL/6 mice (age, 12 weeks) receiving dutasteride (1.8 mg/kg/d)) or vehicle with consumption of a high-fat diet, with or without A-348441, were also studied. In the 5alphaR1-KO mice, hepatic GR antagonism improved diet-induced insulin resistance but not more than that of the controls. Liver steatosis was not affected by hepatic GR antagonism in either 5alphaR1KO mice or littermate controls. In a second model of 5alpha-reductase inhibition using dutasteride and hepatic GR antagonism with A-348441 attenuated the excess weight gain resulting from dutasteride (mean +/- SEM, 7.03 +/- 0.5 vs 2.13 +/- 0.4 g; dutasteride vs dutasteride plus A-348441; P < 0.05) and normalized the associated hyperinsulinemia after glucose challenge (area under the curve, 235.9 +/- 17 vs 329.3 +/- 16 vs 198.4 +/- 25 ng/mL/min; high fat vs high fat plus dutasteride vs high fat plus dutasteride plus A-348441, respectively; P < 0.05). However, A-348441 again did not reverse dutasteride-induced liver steatosis. Thus, overall hepatic GR antagonism improved the insulin resistance but not the steatosis induced by a high-fat diet. Moreover, it attenuated the excessive insulin resistance caused by pharmacological inhibition of 5alpha-reductases but not genetic disruption of 5alphaR1. The use of dutasteride might increase the risk of type 2 diabetes mellitus and reduced exposure to glucocorticoids might be beneficial. |