Lipolytic effects of conventional β₃-adrenoceptor agonists and of CGP 12,177 in rat and human fat cells : preliminary pharmacological evidence for a putative β₄-adrenoceptor

Abstract

1. The nature of rat and human fat cell β₃-adrenoceptors was investigated by studying the effects of the new β₃-adrenoceptor selective antagonist, SR 59,230A, on lipolysis induced by the conventional β₃-adrenoceptor agonists, CL 316,243 and SR 58,611A, and by the non-conventional partial β₃-adrenoceptor agonist CGP 12,177 (a potent β₁- and β₂-adrenoceptor antagonist with partial β₃-adrenoceptor agonist property).

2. In rat fat cells, the rank order of potency of agonists was: CL 316,243>isoprenaline>SR 58,611A>CGP 12,177. The three former agents were full agonists whereas CGP 12,177 was a partial agonist (intrinsic activity of 0.70). In human fat cells, the lipolytic effect of CGP 12,177 reached 25 % of isoprenaline effect. CL 316,243 was a poor inducer of lipolysis and SR 58,611A was ineffective.

3. In rat fat cells, lipolysis induced by CL 316,243 and SR 58,611A was competitively antagonized by SR 59,230A. Schild plots were linear with pA₂ values of 6.89 and 6.37, respectively. Conversely, 0.1, 0.5 and 1 μM SR 59,230A did not modify the concentration-response curve of CGP 12,177. A rightward shift of the curve was however observed with 10 and 100 μM of SR 59,230A. The apparent pA₂ value was 5.65. The non-selective β-adrenergic antagonist, bupranolol, competitively displaced the concentration-response curve of CGP 12,177 and CL 316,243. Schild plots were linear with pA₂ values of 6.70 and 7.59, respectively. CL316,243-mediated lipolytic effect was not antagonized by CGP 20,712A. In human fat cells, CGP 12,177-mediated lipolytic effect was antagonized by bupranolol and CGP 20,712A. SR 59,230A (0.1, 1 and 10 μM) did not modify the concentration-response curve of CGP 12,177. A rightward shift was however observed at 100 μM leading to an apparent pA₂ value of 4.32.

4. The results suggest that the non-conventional partial agonist CGP 12,177 can activate lipolysis in fat cells through the interaction with a β-adrenoceptor pharmacologically distinct from the β₃-adrenoceptor, i.e. through a putative β₄-adrenoceptor. They suggest that the two subtypes coexist in rat fat cells whereas only the putative β₄-adrenoceptor mediates lipolytic effect of CGP12,177 in human fat cells.

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