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

Abstract

1. The β3-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 β-adrenoceptor stimulation were compared in adipose tissues of β3-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 β1-,β2- or β3-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 β3-adrenoceptor knockout mice, the β1- and β2-responses were fully conserved. 3. In BAT of wild type mice, the β1/β2-antagonist and β3-partial agonist CGP 12177 elicited a maximal MO2 response (4.7 ± 0.4 fold). In β3-adrenoceptor knockout BAT, this response was fully conserved despite an absence of response to CL 316,243. This unexpected result suggests that an atypical β-adrenoceptor, distinct from the β1-, β2- and β3-subtypes and referred to as a putative β1-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 β1-, β2- or β3-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 β3-adrenoceptor knockout mice, the lipolytic responses to (-)epinephrine, to the β1-, β2-, β3-adrenoceptor selective agonists and to CGP 12177 were almost or totally depressed, whereas those to ACTH, forskolin and dibutyryl cyclic AMP were conserved.