cAMP-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and PKA-dependent processes

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

^* To whom correspondence should be addressed. Email: kak{at}bmb.sdu.dk.

	Abstract

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 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 pro-adipogenic insulin/insulin-like growth factor-1 (IGF-1) signaling, which was restored by activation of Epac. This interplay between PKA and Epac mediated processes provides not only novel insight into the initiation and tuning of adipocyte differentiation, but also demonstrates a new mechanism of cAMP signaling where cAMP uses both PKA and Epac to achieve an appropriate cellular response.