COEXISTING BETA-ADRENOCEPTOR SUBTYPES - SIGNIFICANCE FOR THERMOGENIC PROCESS IN BROWN FAT-CELLS

The possible significance of the coexisting beta(1)-, beta(2)-, and be ta(3)-adrenoceptors in brown adipose tissue for the thermogenic respon se was investigated. Oxygen consumption of isolated hamster brown fat cells was analyzed as a measure of thermogenesis. Thermogenesis could be evoked not only by the physiological agent norepinephrine but also by BRL-37344 and CGP-12177. No evidence for biphasic inhibition curves was found with either the selective beta(1)-antagonist ICI-89406, the beta(2)-antagonist ICI-118551, or the beta(1)/beta(2)-nonselective be ta-antagonist propranolol against 1 mu M norepinephrine; pI(50) (the n egative logarithm of the inhibitory constant for an antagonist, as est imated from the dose-response curve for an antagonist vs, a constant a gonist concentration) values for ICI-89406 and ICI-118551 were very lo w (4-5), implying nonselective inhibition; the pI(50) for propranolol was similar to 6 (as expected for the beta(3)-receptor). Even with sub optimal norepinephrine, no biphasic inhibition was found. CGP-12177 at concentrations where it is primarily an antagonist to the beta(1)-rec eptor did not influence the dose-response curve for either norepinephr ine or BRL-37344. BRL-37344- or CGP-12177-induced thermogenesis was in hibited by the beta-antagonists in a manner similar to norepinephrine- induced thermogenesis. Schild plots for propranolol inhibition of nore pinephrine-, isoprenaline-, BRL-37344- and CGP-12177-induced thermogen esis yielded similar PA(2) (the negative logarithm of the inhibitory c onstant for an antagonist, as calculated from a series of agonist dose -response curves at different antagonist concentrations) (similar to 5 .5), for interaction with either agonist, implying that the same recep tor was stimulated by all agonists. Thus, despite the fact that differ ent beta-receptor subtypes coexist in the tissue, we find no evidence for the participation of beta(1)- or beta(2)-receptors in the thermoge nic response. Within the resolution of the experiments, the results th erefore imply that it is predominantly or solely the beta(3)-receptor that is coupled to thermogenesis, and it is via this beta-adrenergic r eceptor that not only norepinephrine but also CGP-12177 and BRL-37344 induce thermogenesis.