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Cyclic AMP (cAMP)-Mediated Stimulation of Adipocyte Differentiation Requires the Synergistic Action of Epac- and cAMP-Dependent Protein Kinase-Dependent Processes

Rasmus Koefoed Petersen,^2, Lise Madsen,^1,3,4, Lone Møller Pedersen,¹ Philip Hallenborg,¹ Hanne Hagland,³ Kristin Viste,³ Stein Ove Døskeland,³ and Karsten Kristiansen^1*

Department of Biochemistry and Molecular Biology, University of Southern Denmark, DK-5230 Odense M, Denmark,¹ BioLigands, International Science Park Odense, DK-5230 Odense M, Denmark,² Department of Biomedicine, University of Bergen, N-5009 Bergen, Norway,³ National Institute of Nutrition and Seafood Research, 5817 Bergen, Norway⁴

Received 23 April 2007/ Returned for modification 23 July 2007/ Accepted 17 March 2008

Cyclic AMP (cAMP)-dependent processes are pivotal during the early stages of adipocyte differentiation. We show that exchange protein directly activated by cAMP (Epac), which functions as a guanine nucleotide exchange factor for the Ras-like GTPases Rap1 and Rap2, was required for cAMP-dependent stimulation of adipocyte differentiation. Epac, working via Rap, acted synergistically with cAMP-dependent protein kinase (protein kinase A [PKA]) to promote adipogenesis. The major role of PKA was to down-regulate Rho and Rho-kinase activity, rather than to enhance CREB phosphorylation. Suppression of Rho-kinase impaired proadipogenic insulin/insulin-like growth factor 1 signaling, which was restored by activation of Epac. This interplay between PKA and Epac-mediated processes not only provides novel insight into the initiation and tuning of adipocyte differentiation, but also demonstrates a new mechanism of cAMP signaling whereby cAMP uses both PKA and Epac to achieve an appropriate cellular response.

Published ahead of print on 7 April 2008.

R.K.P. and L.M. contributed equally to this work.