TRIIODOTHYRONINE AND AMIODARONE EFFECTS ON BETA(3)-ADRENOCEPTOR DENSITY AND LIPOLYTIC RESPONSE TO THE BETA(3)-ADRENERGIC AGONIST BRL-37344 IN RAT WHITE ADIPOCYTES

The beta-adrenergic effects of catecholamines are potentiated by thyro id hormones in adipose tissue. Amiodarone (AM) is structurally similar to thyroid hormones and was used to explore the mechanism of the trii odothyronine (T-3) effect on beta-adrenergic receptors (beta-ARs) in a dipose tissue. AM decreases the expression of some T-3 sensitive genes in various tissues and antagonizes the effect of T-3 on its nuclear r eceptors. In this study, the T-3, AM and AM + T-3 effects on the beta 1- and beta(3)-AR density were assessed on rat white adipocytes by rad ioligand binding using [H-3]CGP 12177 after characterization of these subtypes by displacement of [H-3]CGP 12177 binding by isoproterenol, B RL 37344 and noradrenaline. BRL 37344 was used to study beta(3)-AR lip olysis. White adipocytes from hyperthyroid rats had increased responsi veness (E(max) x 2) and sensitivity (+ 38%) to BRL 37344, while those given AM alone had decreased values. Moreover, AM antagonized the T-3 effect on lipolysis. The beta(1)-binding characteristics (receptor den sity [B-max]; 45 +/- 4 fmol/mg of proteins: dissociation factor [K-d]: 0.96 +/- 0.10 nM) were not modified by either compound. Finally, T-3 significantly increased increased beta(3)-AR density (587 +/- 69 versu s 363 +/- 25 fmol/mg of proteins) and K-d (38 +/- 2 versus 23 +/- 3 nM ), while AM alone had no effect and did not antagonize the T-3 effect on beta(3)-AR number. In conclusion, the hyperthyroid state in the rat potentiated the lipolytic response of white adipocytes to a specific beta(3)-agonist and increased the beta(3)-AR density without changing in beta(1)-AR number and affinity. Furthermore, the lack of antagonism between AM and T-3 on beta(3)-AR expression suggests that T-3 does no t work directly on the beta(3)-AR gene. Moreover, AM induced a functio nal tissular hypothyroid-like effect and its antilipolytic effect prob ably occurred at a postreceptor level.