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J. Biol. Chem., Vol. 281, Issue 49, 37794-37802, December 8, 2006

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Maximal ₃-Adrenergic Regulation of Lipolysis Involves Src and Epidermal Growth Factor Receptor-dependent ERK1/2 Activation^*

Jacques Robidoux, Naresh Kumar, Kiefer W. Daniel, Fatiha Moukdar, Michel Cyr, Alexander V. Medvedev^¶, and Sheila Collins^¶1

From the Program in Endocrine Biology, Division of Biological Sciences, CIIT Centers for Health Research, Research Triangle Park, North Carolina 27709 and ^¶Departments of Psychiatry and Behavioral Sciences and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

Catecholamine-stimulated lipolysis is primarily a -adrenergic and cAMP-dependent event. In previous studies we established that the ₃-adrenergic receptor (₃AR) in adipocytes utilizes a unique mechanism to stimulate extracellular signal-regulated kinases 1 and 2 (ERK) by direct recruitment and activation of Src kinase. Therefore, we investigated the role of the ERK pathway in adipocyte metabolism and found that the ₃AR agonist CL316,243 regulates lipolysis through both cAMP-dependent protein kinase (PKA) and ERK. Inhibition of PKA activity completely eliminated lipolysis at low (subnanomolar) CL316,243 concentrations and by 75-80% at higher nanomolar concentrations. The remaining 20-25% of PKA-independent lipolysis, as well as ERK activation, was abolished by inhibiting the activity of either Src (PP2 or small interfering RNA), epidermal growth factor receptor (EGFR with AG1478 or small interfering RNA), or mitogen-activated protein kinase kinase 1 or 2 (MKK1/2 with PD098059). PD098059 inhibited lipolysis by 53% in mice as well. Finally, the effect of estradiol, a reported acute activator of ERK and lipolysis, was also totally prevented by PP2, AG1478, and PD098059. These results suggest that ERK activation by ₃AR depends upon Src and epidermal growth factor receptor kinase activities and is responsible for the PKA-independent portion of the lipolytic response. Together these results illustrate the distinct and complementary roles for PKA and ERK in catecholamine-stimulated lipolysis.

Received for publication, June 9, 2006 , and in revised form, October 4, 2006.

^* This work was supported by National Institutes of Health Grant R01-DK57698 (to S. C.) and a fellowship from Fonds de la Recherche en Santé du Québec (to J. R.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: CIIT Centers for Health Research, 6 Davis Dr., Box 12137, Research Triangle Park, NC 27709. Tel.: 919-558-1378; Fax: 919-558-1305; E-mail: scollins{at}ciit.org.

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