EVIDENCE FOR A FUNCTIONAL BETA(3)-ADRENOCEPTOR IN MAN

1 The existence of a functional beta3-adrenoceptor in man was investig ated by studying the lipolytic action of selective beta-adrenoceptor a gents in isolated white omental and subcutaneous fat cells. 2 The non- selective beta1/beta2-adrenoceptor antagonist, CGP 12177 was lipolytic in both omental and subcutaneous fat cells. The intrinsic activity re lative to isoprenaline was greater in omental than in subcutaneous cel ls. 3 Addition of the beta2-adrenoceptor antagonist, ICI 118,551 and t he beta1-adrenoceptor antagonist CGP20712A in combination or the non-s elective beta-adrenoceptor antagonist propranolol alone (all 10(-7) M) , induced a rightward shift of the dose-response curves for isoprenali ne- and BRL37344-stimulated lipolysis of about 4 and 2 log-units, resp ectively. However, the antagonists did not alter lipolysis induced by CGP12177. 4 Several concentrations of beta-adrenoceptor antagonists we re used to determine the pA2 values by Schild analysis. The values for CGP 20712A and ICI 118,551 (6.63 +/- 0.20 and 6.25 +/- 0.12) as antag onists of the lipolytic effects of CGP 12177 were over 2 units lower t han the pA2 value for CGP 20712A against the response to the selective beta1-agonist dobutamine (8.58 +/- 0.23) and the pA2 value for ICI 11 8,551 against the response to the selective beta2-agonist terbutaline (9.15 +/- 0.26). 5 Beta3-adrenoceptor mRNA expression, investigated wi th a polymerase chain reaction assay, was demonstrated in both types o f adipocytes in the same cell preparations that had a lipolytic respon se to CGP 12177. 6 In conclusion, human white fat cells express an aty pical beta-adrenoceptor in addition to beta1- and beta2-adrenoceptors. This receptor is stimulated more selectively by the beta1-/beta2-anta gonist CGP 12177 than by BRL 37344 and is poorly sensitive to blockade by selective beta1- and beta2-antagonists. On the basis of the pharma cological properties and the mRNA analyses, we suggest that this atypi cal receptor corresponds to the beta3-adrenoceptor subtype.