Evidence for a functional β3‐adrenoceptor in man

1 The existence of a functional β3‐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 β1/β2‐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 β2‐adrenoceptor antagonist, ICI 118,551 and the β1‐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 pA2 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 pA2 value for CGP 20712A against the response to the selective β1‐agonist dobutamine (8.58 ± 0.23) and the pA2 value for ICI 118,551 against the response to the selective β2‐agonist terbutaline (9.15 ± 0.26). 5 β3‐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 β1‐ and β2‐adrenoceptors. This receptor is stimulated more selectively by the β1‐/β2‐antagonist CGP 12177 than by BRL 37344 and is poorly sensitive to blockade by selective β1‐ and β2‐antagonists. On the basis of the pharmacological properties and the mRNA analyses, we suggest that this atypical receptor corresponds to the β3‐adrenoceptor subtype.