Coexistence of beta 1-, beta 2-, and beta 3-adrenoceptors in dog fat cells and their differential activation by catecholamines

The existence of a beta 3-adrenoceptor (in addition to classical beta 1- and beta 2-), its involvement in the control of lipolysis and its recruitment by catecholamines were investigated in dog adipose tissue. Isoproterenol, norepinephrine, and the beta 2-selective agonist procaterol fully activated lipolysis in adipocytes (order of potency: isoproterenol > norepinephrine = procaterol). beta 3-Adrenergic agonists stimulated lipolysis with the order of potency: BRL 37344 > CGP 12177 > SR 58611A. Propranolol and bupranolol (nonselective beta-antagonists) antagonized, with a low potency, the effect of BRL 37344, whereas the beta 1-antagonist CGP 20712A and the beta 2-antagonist ICI 118551 were without action. CGP 20712A inhibited the effect of lower concentrations of agonists (0.05 microM isoproterenol, 0.1 microM norepinephrine and 0.1 microM procaterol) with an inhibitory constant (mean Ki) of 0.0075, 0.032 and > 10 microM, respectively. Mean Ki values for the beta 2-antagonist ICI 118551 were 1.744, 1.243, and 0.019 microM. This result indicates that low concentrations of isoproterenol and norepinephrine stimulate lipolysis mainly via beta 1-adrenoceptors in dog fat cells. Inversely, the lipolytic effect of higher concentrations of agonists i.e., 1 microM isoproterenol and catecholamines, was weakly antagonized by CGP 20712A or ICI 118551 while the nonselective beta-antagonists bupranolol and propranolol suppressed the effects with the order of potency expected for a beta 3-adrenoceptor: bupranolol > propranolol. These data indicate 1) the presence of a functional beta 3-adrenoceptor that coexists with beta 1- and beta 2-adrenoceptors in dog fat cells; 2) a separation of the differential potencies of physiological amines in the activation of lipolysis through beta 1-, beta 2-, and beta 3-adrenoceptors; the lipolytic response initiated at low concentrations (submicromolar range) of norepinephrine is primarily mediated by the beta 1-adrenoceptor subtype; and 3) an activation of the beta 3-adrenoceptor that occurs at higher concentrations of catecholamines.