Metabolic response to various β-adrenoceptor agonists in β3-adrenoceptor knockout mice:: Evidence for a new β-adrenergic receptor in brown adipose tissue

1 The beta(3)-adrenoceptor plays an important role in the adrenergic response of brown and white adipose tissues (BAT and WAT). In this study, in vitro metabolic responses to beta-adrenoceptor stimulation were compared in adipose tissues of beta(3)-adrenoceptor knockout and wild type mice. The measured parameters were BAT fragment oxygen uptake (MO2) and isolated white adipocyte lipolysis. 2 In BAT of wild type mice (-)-norepinephrine maximally stimulated MO2 4.1+/-0.8 fold. Similar maximal stimulations were obtained with beta(1)-,beta(2)- or beta(3)-adrenoceptor selective agonists (dobutamine 5. 1+/-0.3, terbutaline 5.3+/-0.3 and CL 316,243 4.8+/-0.9 fold, respectively); in BAT of beta(3)-adrenoceptor knockout mice, the beta(1)- and beta(2)-responses were fully conserved. 3 In BAT of wild type mice, the beta(1)/beta(2)-antagonist and beta(3)-partial agonist CGP 12177 elicited a maximal MO2 response (4.7+/-0.4 fold). In beta(3)-adrenoceptor knockout BAT, this response was fully conserved despite an absence of response to CL 316,243. This unexpected result suggests that an atypical beta-adrenoceptor, distinct from the beta(1)-, beta(2)- and beta(3)-subtypes and referred to as a putative beta(4)-adrenoceptor is present in BAT and that it can mediate in vitro a maximal MO2 stimulation. 4 In isolated white adipocytes of wild type mice, (-)-epinephrine maximally stimulated lipolysis 12.1+/-2.6 fold. Similar maximal stimulations were obtained with beta(1)-, beta(2)- or beta(3)-adrenoceptor selective agonists (TO509 12+/-2, procaterol 11+/-3, CL 316,243 11+/-3 fold, respectively) or with CGP 12177 (7.1+/-1.5 fold). In isolated white adipocytes of beta(3)-adrenoceptor knockout mice, the lipolytic responses to (-)epinephrine, to the beta(1)-, beta(2)-, beta(3)-adrenoceptor selective agonists and to CGP 12177 were almost or totally depressed, whereas those to ACTH, forskolin and dibutyryl cyclic AMP were conserved.