Differential adrenergic regulation of the gene expression of the β-adrenoceptor subtypes β1, β2 and β3 in brown adipocytes

Abstract

In brown adipocytes, fundamental cellular processes (cell proliferation, differentiation and apoptosis) are regulated by adrenergic stimulation, notably through β-adrenergic receptors. The presence of all three β-receptor subtypes has been demonstrated in brown adipose tissue. Due to the significance of the action of these receptors and indications that the subtypes govern different processes, the adrenergic regulation of the expression of the β1-, β2- and β3-adrenoceptor genes was examined in murine brown-fat primary cell cultures. Moderate levels of β1-receptor mRNA, absence of β2-receptor mRNA and high levels of β3-receptor mRNA were observed in mature brown adipocytes (day 6 in culture). Noradrenaline (norepinephrine) addition led to diametrically opposite effects on β1- (markedly enhanced expression) and β3-gene expression (full cessation of expression, as previously shown). β2-Gene expression was induced by noradrenaline, but only transiently (< 1 h). The apparent affinities (EC50) of noradrenaline were clearly different (7 nM for the β1-gene and≤ 1 nM for the β3-gene), as were the mediation pathways (solely via β3-receptors and cAMP for the β1-gene and via β3-receptors and cAMP, as well as via α1-receptors and protein kinase C, for the β3-gene). The half-lives of the corresponding mRNA species were very short but different (17 min for β1-mRNA and 27 min for β3-mRNA), and these degradation rates were not affected by noradrenaline, implying that the mRNA levels were controlled by transcription. Inhibition of protein synthesis also led to diametrically opposite effects on β1- and β3-gene expression, but - notably - these effects were congruent with the noradrenaline effects, implying that a common factor regulating β1-gene expression negatively and β3-gene expression positively could be envisaged. In conclusion, very divergent effects of adrenergic stimulation on the expression of the different β-receptor genes were found within one cell type, and no unifying concept of adrenergic control of β-receptor gene expression can be formulated, either concerning different cell types, or concerning the different β-receptor subtype genes.