Evidence for a functional β 3 ‐adrenoceptor in man

1 The existence of a functional β 3 ‐adrenoceptor in man was investigated by studying the lipolytic action of selective β‐adrenoceptor agents in isolated white omental and subcutaneous fat cells. 2 The non‐selective β 1 /β 2 ‐adrenoceptor antagonist, CGP 12177 was lipolytic in both omental and subcutaneous fat cells. The intrinsic activity relative to isoprenaline was greater in omental than in subcutaneous cells. 3 Addition of the β 2 ‐adrenoceptor antagonist, ICI 118,551 and the β 1 ‐adrenoceptor antagonist CGP20712A in combination or the non‐selective β‐adrenoceptor antagonist propranolol alone (all 10 −7 m ), induced a rightward shift of the dose‐response curves for isoprenaline‐ and BRL37344‐stimulated lipolysis of about 4 and 2 log‐units, respectively. However, the antagonists did not alter lipolysis induced by CGP12177. 4 Several concentrations of β‐adrenoceptor antagonists were used to determine the pA 2 values by Schild analysis. The values for CGP 20712A and ICI 118,551 (6.63 ± 0.20 and 6.25 ± 0.12) as antagonists of the lipolytic effects of CGP 12177 were over 2 units lower than the pA 2 value for CGP 20712A against the response to the selective β 1 ‐agonist dobutamine (8.58 ± 0.23) and the pA 2 value for ICI 118,551 against the response to the selective β 2 ‐agonist terbutaline (9.15 ± 0.26). 5 β 3 ‐Adrenoceptor mRNA expression, investigated with a polymerase chain reaction assay, was demonstrated in both types of adipocytes in the same cell preparations that had a lipolytic response to CGP 12177. 6 In conclusion, human white fat cells express an atypical β‐adrenoceptor in addition to β 1 ‐ and β 2 ‐adrenoceptors. This receptor is stimulated more selectively by the β 1 ‐/β 2 ‐antagonist CGP 12177 than by BRL 37344 and is poorly sensitive to blockade by selective β 1 ‐ and β 2 ‐antagonists. On the basis of the pharmacological properties and the mRNA analyses, we suggest that this atypical receptor corresponds to the β 3 ‐adrenoceptor subtype.