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 β₄-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.

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