Role of Hepatic Glucocorticoid Receptor in Metabolism in Models of 5αR1 Deficiency in Male Mice.

Abstract

Inhibition of 5α-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 5α-reductase 1 (5αR1-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 5αR1-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 5αR1KO mice or littermate controls. In a second model of 5α-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 5α-reductases but not genetic disruption of 5αR1. The use of dutasteride might increase the risk of type 2 diabetes mellitus and reduced exposure to glucocorticoids might be beneficial.

• Authors: Tracy C S Mak, Dawn E W Livingstone, Mark Nixon, Brian R Walker, Ruth Andrew
• Journal: Endocrinology (Endocrinology) Vol. 160 Issue 9 Pg. 2061-2073 (09 01 2019) ISSN: 1945-7170 [Electronic] United States
• PMID: 31199473 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• (3b,5b,7a,12a)-7,12-dihydroxy-3-(2-((4-((11b,17b)-17-hydroxy-3-oxo-17-prop-1-ynylestra-4,9-dien-11-yl) phenyl)(methyl)amino)ethoxy)cholan-24-oic acid
• Cholic Acids
• Receptors, Glucocorticoid
• Estrone
• Cholestenone 5 alpha-Reductase
• Dutasteride

Topics

• Animals
• Cholestenone 5 alpha-Reductase (deficiency, physiology)
• Cholic Acids (pharmacology)
• Diet, High-Fat
• Dutasteride (pharmacology)
• Estrone (analogs & derivatives, pharmacology)
• Gluconeogenesis
• Insulin Resistance
• Lipid Metabolism
• Liver (physiology)
• Male
• Mice
• Mice, Inbred C57BL
• Receptors, Glucocorticoid (physiology)