RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient β-adrenergic signalling in adipocytes from mature C57BL/6J-ob/ob mice

Abstract

OBJECTIVE: To investigate the role of hypercorticism in the development of compromised β-adrenergic signalling in adipocytes of mature C57BL/6J-ob/ob mice. DESIGN AND EXPERIMENTAL UNITS: Mature male ob/ob mice and their lean littermates were treated with vehicle or the specific glucocorticoid receptor (GR) antagonist, RU-486 (30 mg/kg bw/d) for 21 d. MEASUREMENTS: Blood glucose, serum insulin, adipocyte Glut-4 expression, adipocyte G_sα expression, adenylylcyclase activation by β-adrenergic receptor (β-AR) agonists in adipocyte membranes and mRNA levels for β₁-, β₂- and β₃-adrenergic receptor subtypes in adipocytes. RESULTS: RU-486 reduced blood glucose levels in ob/ob mice to levels that were not different from lean mice. RU-486 also reduced serum insulin by approximately 50% in ob/ob mice, but failed to restore depressed G_sα or GLUT-4 expression in adipocytes of ob/ob mice. RU-486 produced a two-fold increase in β₃-AR mRNA in ob/ob mice and a small but significant improvement in isoprenaline-mediated adenylylcyclase activation. CONCLUSIONS: The present results indicate that glucocorticoid antagonism ameliorates diabetic symptoms of the mature ob/ob mouse, but does not lessen their obesity or fully reverse deficient expression and function of components of the adipocyte β-adrenergic signalling cascade.