Desensitization of beta-adrenergic responses in adipocytes involves receptor subtypes and cAMP phosphodiesterase.
Acute exposure of isolated adipocytes to isoproterenol induces the desensitization of lipolytic responses to norepinephrine and selective beta 1-, beta 2- and beta 3-adrenoceptor agonists, as well as the adrenocorticotropic hormone 1-24 fragment (ACTH). Forskolin and 8-bromo-cAMP responses are also desensitized. When lipolysis was measured in the presence of OPC 3911 [N-cyclohexyl-N-2-hydroxyethyl-4(6-(1,2-dihydro-2- oxoquinolyloxy))butyramide], a specific inhibitor of the cAMP phosphodiesterase of adipocytes, the desensitization of all lipolytic agents--except the beta 2-adrenoceptor agonist--was abolished. Isoproterenol induced a similar loss (35%) of both membrane beta 1- and beta 2-adrenoceptors and an uncoupling of beta 1-adrenoceptors, but did not modify the weak coupling of control beta 2-adrenoceptors. These data suggest that isoproterenol induced (i) an activation of the cAMP phosphodiesterase, which is solely responsible for the desensitization of norepinephrine response as well as beta 1- and beta 3-adrenoceptor mediated responses and (ii) an additional desensitization of the sole beta 2-adrenergic signaling system which suggests a subtype-selective pattern of regulating processes.
Bousquet-Mélou
A
A
Institut National de la Santé et de la Recherche Médicale Unité 317, Faculté de Médicine, Université Paul Sabatier, Toulouse, France.
Galitzky
J
J
Moreno
C M
CM
Berlan
M
M
Lafontan
M
M
D017667:Adipocytes / Q000187:drug effects*; D000818:Animals; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects*; D017265:Procaterol / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D004280:Dobutamine; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D007545:Isoproterenol; D009638:Norepinephrine; D017265:Procaterol