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Endocrinology Vol. 140, No. 9 4185-4197
Copyright © 1999 by The Endocrine Society

ARTICLES

ß1 to ß3 Switch in Control of Cyclic Adenosine Monophosphate during Brown Adipocyte Development Explains Distinct ß-Adrenoceptor Subtype Mediation of Proliferation and Differentiation1

Gennady Bronnikov2,3, Tore Bengtsson, Ludmila Kramarova2, Valeria Golozoubova, Barbara Cannon and Jan Nedergaard

The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, S-106 91 Stockholm, Sweden

Address all correspondence and requests for reprints to: Jan Nedergaard, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, SE-106 91 Stockholm, Sweden. E-mail: jan{at}metabol.su.se

To explain the distinctive pharmacological profiles observed for adrenergic stimulation of cell proliferation (ß1) and cell differentiation (ß3), the adrenergic control of cAMP accumulation was investigated during brown adipocyte development. In preadipocytes, norepinephrine (NE) increased cAMP levels but the ß3-agonists BRL-37344 and CGP-12177 did not; in contrast, when the cells had differentiated into mature brown adipocytes, a large cAMP response to the ß3-agonists had emerged and was now double that to NE (although the affinity of NE had increased 10-fold). ß1-messenger RNA (mRNA) levels were high in both pre- and mature brown adipocytes; ß3-mRNA did not appear until maturation but then abruptly. Although ß1-receptors remained detectable by [3H]CGP-12177 binding in the mature brown adipocytes, the cAMP response to NE (based on propranolol inhibitory potency) switched from ß1 to ß3. Even the established ß1-agonist dobutamine acted through ß3-receptors in the mature brown adipocytes. The increases in cAMP levels could adequately explain the increased cell proliferation in NE-stimulated preadipocytes and the NE-induced UCP1 gene expression in mature brown adipocytes. The distinctive adrenergic profiles for stimulation of proliferation and of differentiation were thus not due to the existence of additional pathways but to a switch in the type of ß-receptor mediating the NE response, coordinated with an alteration in the nuclear response to increased cAMP levels. The study implies that full recruitment of brown adipose tissue cannot be induced by exclusive ß3-stimulation.




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