Correlation of beta 3-adrenoceptor-induced activation of cyclic AMP-dependent protein kinase with activation of lipolysis in rat white adipocytes.
The lipolytic action of the beta 3-adrenoceptor-selective agonist 4-[2-[(2-hydroxy-2-(3-chlorophenyl)ethyl)-amino]propyl]-phenoxyacetic acid (BRL 37344) was compared to that of isoprenaline in adipocytes derived from rat white adipose tissue. Concentration-response curves for activation of lipolysis by each agonist correlated well with the dose-response curves for activation of cAMP-dependent protein kinase (A-Kinase). Addition of propranolol at a concentration (0.1 microM) sufficient to block beta 1- and beta 2-adrenoceptors did not affect the stimulation of either parameter by BRL 37344 or isoprenaline, indicating that lipolysis was predominantly dependent on beta 3-adrenoceptor stimulation. Blockade of beta 3-adrenoceptors by 3 microM propranolol antagonized both A-Kinase activation and glycerol release. Activation of lipolysis by BRL 37344 was blocked by treatment of the cells with N-[2-p-(bromocinnamylamino)ethyl]-5-isoquinolinesulphonamide (H89) a potent and selective isoquinolinesulphonamide inhibitor of A-Kinase activity. Taken together, these results indicate that lipolysis in rat white adipocytes is primarily controlled by beta 3-adrenoceptors, and that cyclic AMP generation alone is responsible for activation of lipolysis in this tissue.
Murphy
G J
GJ
Diabetes Programme, SmithKline Beecham Pharmaceuticals Research Division, Epsom, Surrey, U.K.
Kirkham
D M
DM
Cawthorne
M A
MA
Young
P
P
D000262:Adenylyl Cyclases / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation; D004983:Ethanolamines / Q000494:pharmacology; D005990:Glycerol / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis; D008969:Molecular Sequence Data; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013379:Substrate Specificity
D000318:Adrenergic beta-Agonists; D004983:Ethanolamines; D011943:Receptors, Adrenergic, beta; C057368:BRL 37344; D000242:Cyclic AMP; D011494:Protein Kinases; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D005990:Glycerol