RU-486 (MIFEPRISTONE) AMELIORATES DIABETES BUT DOES NOT CORRECT DEFICIENT BETA-ADRENERGIC SIGNALING IN ADIPOCYTES FROM MATURE C57BL 6J-OB/OB MICE/

OBJECTIVE: To investigate the role of hypercorticism in the developmen t of compromised beta-adrenergic signalling in adipocytes of mature C5 7BL/6J-ob/ob mice. DESIGN AND EXPERIMENTAL UNITS: Mature male ob/ob mi ce and their lean littermates were treated with vehicle or the specifi c glucocorticoid receptor (GR) antagonist, RU-486 (30 mg/kg bw/d) for 21 d. MEASUREMENTS: Blood glucose, serum insulin, adipocyte Glut-4 exp ression, adipocyte G(s) alpha expression, adenylylcyclase activation b y beta-adrenergic receptor (beta-AR) agonists in adipocyte membranes a nd mRNA levels for beta(1)-, beta(2)- and beta(3)-adrenergic receptor subtypes in adipocytes. RESULTS: RU-486 reduced blood glucose levels i n 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 fai led to restore depressed G(s) alpha or GLUT-4 expression in adipocytes of ob/ob mice. RU-486 produced a two-fold increase in beta(3)-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 adipoc yte beta-adrenergic signalling cascade.