Noradrenaline Induces Brown Adipocytes Cell Growth via -Receptors by a Mechanism Dependent on ERKs but Independent of cAMP and PKA AMPARO VALLADARES, 1 ALMUDENA PORRAS, 1 * ALBERTO M. A ´ LVAREZ, 2 CESAR RONCERO, 1 AND MANUEL BENITO 1 1 Departamento de Bioquı ´mica y Biologı ´a Molecular II, Instituto de Bioquı ´mica, Centro Mixto del Consejo Superior de Investigaciones Cientı ´ficas y de la Universidad Complutense de Madrid, Madrid, Spain 2 Centro de Citometrı ´a de Flujo y Microscopı ´a Confocal, Universidad Complutense de Madrid, Facultad de Farmacia, Universidad Complutense, Ciudad Universitaria, Madrid, Spain It has been well established that the key role of noradrenaline is the induction of uncoupling-protein-1 (UCP-1) expression, the unique marker of brown adipo- cytes. However, its implication on proliferation and the pathways involved are not as well characterized. By using rat fetal brown adipocytes as a model, we show that, although noradrenaline activates extracellular regulated kinases (ERKs) through -, 1-, and 2-receptors, only -receptors mediate cell growth by a mechanism that requires ERKs activation but is independent of cyclic-adenosine- monophosphate/protein kinase A (cAMP/PKA). Conversely, the cAMP/PKA cas- cade mediates noradrenaline-induced UCP-1 expression, whereas ERKs pathway attenuates thermogenic differentiation. On the other hand, 1- and 2-receptors have an antiproliferative effect that is enhanced by ERK inhibition. J. Cell. Physiol. 185:324 –330, 2000. © 2000 Wiley-Liss, Inc. The major function of brown adipose tissue (BAT) is to generate heat by a mechanism called “nonshivering thermogenesis” to regulate body temperature and weight. This process is carried out by the uncoupling protein-1 (UCP-1), which uncouples the mitochondrial respiratory chain from oxidative phosphorylation, so that energy, instead of being used for ATP production, is dissipated as heat. BAT is only active under certain circumstances such as in the perinatal period in mam- mals, after cold exposure, and in animals fed with hypercaloric diets (Trayhurn and Milner, 1989; Porras et al., 1990) During the perinatal period in the rat, a recruitment of BAT is produced which is characterized by an in- crease in the number of cells, mitochondria, and UCP-1 content. UCP-1 is already expressed in rat fetal brown adipocytes, and this expression increases after birth (Porras et al., 1990). Insulin-like growth factor 1 (IGF-I) (Lorenzo et al., 1993, Guerra et al., 1994a, Porras et al., 1996), insulin (Teruel et al., 1996), and triiodo thyronine (T3) (Guerra et al., 1994b, 1996) are positive regulators of this process. In addition, nor- adrenaline (NA), which is known to mediate activation and recruitment of BAT in animals exposed to cold (Bukowiecki et al., 1986; Trayhurn et al., 1989), might also play a role in newborn mammals. NA, mainly through -receptors, activates proliferation (Bronnikov et al., 1992; Kozak and Kozak, 1994), induces UCP-1 expression (Porras et al., 1989; Rehmark et al., 1990; Kozak and Kozak, 1994; Rohlfs et al., 1995), and pro- motes cell survival (Briscini et al., 1998; Lindquist and Rehnmark, 1998). NA actions in BAT are mediated by - (-1, -2, and -3), -2-, and -1-adrenergic receptors (Porras et al., 1989; Rehmark et al., 1990; Bronnikov et al., 1992; Kozak and Kozak, 1994; Rohlfs et al., 1995; Zhao et al., 1997) through the activation of different heterotrimeric G proteins. These receptors are known to activate differ- ent signaling pathways including extracellular regu- lated kinase1/2 (ERK1/2, also called p44/p42MAPKs) in many cell types (Alblas et al., 1993; Crespo et al., 1995; van Biesen et al., 1996; Daaka et al., 1997; Gut- kind, 1998). In brown adipocytes from newborn rats (Shimizu et al., 1997) and from adult mice (Lindquist and Rehnmark, 1998), NA also activated ERKs mainly via -receptors, with low contribution of 1-receptors. However, no data are yet available about the role of 2-receptors in ERKs activation in these cells. Signaling through ERKs has been implicated in cell proliferation, differentiation, and/or survival (Page `s et Contract grant sponsor: Comisio ´n Interministerial de Ciencia y Tecnologı ´a from Spain; Contract grant number: SAF97– 0137. *Correspondence to: A. Porras, Departamento de Bioquı ´mica y Biologı ´a Molecular II, Instituto de Bioquı ´mica, Centro Mixto del Consejo Superior de Investigaciones Cientı ´ficas y de la Univer- sidad Complutense de Madrid, 28040 Madrid, Spain. E-mail: maporras @eucmax.sim.ucm.es Received 7 February 2000; Accepted 19 June 2000 JOURNAL OF CELLULAR PHYSIOLOGY 185:324 –330 (2000) © 2000 WILEY-LISS, INC.