Differential adrenergic regulation of the gene expression of the beta-adrenoceptor subtypes beta1, beta2 and beta3 in brown adipocytes.
In brown adipocytes, fundamental cellular processes (cell proliferation, differentiation and apoptosis) are regulated by adrenergic stimulation, notably through beta-adrenergic receptors. The presence of all three beta-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 beta(1)-(,) beta(2)- and beta(3)-adrenoceptor genes was examined in murine brown-fat primary cell cultures. Moderate levels of beta(1)-receptor mRNA, absence of beta(2)-receptor mRNA and high levels of beta(3)-receptor mRNA were observed in mature brown adipocytes (day 6 in culture). Noradrenaline (norepinephrine) addition led to diametrically opposite effects on beta(1)- (markedly enhanced expression) and beta(3)-gene expression (full cessation of expression, as previously shown). beta(2)-Gene expression was induced by noradrenaline, but only transiently (<1 h). The apparent affinities (EC(50)) of noradrenaline were clearly different (7 nM for the beta(1)-gene and</=1 nM for the beta(3)-gene), as were the mediation pathways (solely via beta(3)-receptors and cAMP for the beta(1)-gene and via beta(3)-receptors and cAMP, as well as via alpha(1)-receptors and protein kinase C, for the beta(3)-gene). The half-lives of the corresponding mRNA species were very short but different (17 min for beta(1)-mRNA and 27 min for beta(3)-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 beta(1)- and beta(3)-gene expression, but - notably - these effects were congruent with the noradrenaline effects, implying that a common factor regulating beta(1)-gene expression negatively and beta(3)-gene expression positively could be envisaged. In conclusion, very divergent effects of adrenergic stimulation on the expression of the different beta-receptor genes were found within one cell type, and no unifying concept of adrenergic control of beta-receptor gene expression can be formulated, either concerning different cell types, or concerning the different beta-receptor subtype genes.
Bengtsson
T
T
The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, S-106 91 Stockholm, Sweden. tore.bengtsson@zoofys.su.se
Cannon
B
B
Nedergaard
J
J
D002001:Adipose Tissue, Brown / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D018663:Adrenergic Agents / Q000494:pharmacology*; D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D003080:Cold Temperature; D000242:Cyclic AMP / Q000378:metabolism / Q000494:pharmacology; D003513:Cycloheximide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D006207:Half-Life; D008297:Male; D051379:Mice; D009638:Norepinephrine / Q000819:agonists / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D018342:Receptors, Adrenergic, beta-1 / Q000235:genetics; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics; D022702:Receptors, Adrenergic, beta-3; D014158:Transcription, Genetic / Q000187:drug effects
D018663:Adrenergic Agents; D058665:Adrenergic beta-1 Receptor Agonists; D058671:Adrenergic beta-1 Receptor Antagonists; D058666:Adrenergic beta-2 Receptor Agonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D012333:RNA, Messenger; D011943:Receptors, Adrenergic, beta; D018342:Receptors, Adrenergic, beta-1; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D003513:Cycloheximide; D000242:Cyclic AMP; D011493:Protein Kinase C; D009638:Norepinephrine