RU-486 (Mifepristone) ameliorates diabetes but does not correct deficient beta-adrenergic signalling in adipocytes from mature C57BL/6J-ob/ob mice.
OBJECTIVE
To investigate the role of hypercorticism in the development of compromised beta-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.


METHODS
Blood glucose, serum insulin, adipocyte Glut-4 expression, adipocyte Gs alpha expression, adenylylcyclase activation by beta-adrenergic receptor (beta-AR) agonists in adipocyte membranes and mRNA levels for beta 1-, beta 2- and beta 3-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 Gs 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 adipocyte beta-adrenergic signalling cascade.
Gettys
T W
TW
Department of Medicine, Medical University of South Carolina, Charleston 29425, USA.
Watson
P M
PM
Taylor
I L
IL
Collins
S
S
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D015153:Blotting, Western; D005576:Colforsin / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004983:Ethanolamines / Q000494:pharmacology; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000378:metabolism; D051275:Glucose Transporter Type 4; D006727:Hormone Antagonists / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015735:Mifepristone / Q000494:pharmacology*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D010641:Phenotype; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D001786:Blood Glucose; D004983:Ethanolamines; D051275:Glucose Transporter Type 4; D006727:Hormone Antagonists; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011943:Receptors, Adrenergic, beta; D011965:Receptors, Glucocorticoid; C495693:Slc2a4 protein, mouse; D005576:Colforsin; D015735:Mifepristone; C057368:BRL 37344; D019205:GTP-Binding Protein alpha Subunits, Gs; D000262:Adenylyl Cyclases; D007545:Isoproterenol