Cyclic AMP (cAMP)-mediated stimulation of adipocyte differentiation requires the synergistic action of Epac- and cAMP-dependent protein kinase-dependent processes

Rasmus Koefoed Petersen, Lise Madsen, Lone Møller Pedersen, Philip Hallenborg, Hanne Hagland, Kristin Viste, Stein Ove Døskeland, Karsten Kristiansen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

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.
Original languageEnglish
JournalMolecular and Cellular Biology
Volume28
Issue number11
Pages (from-to)3804-3816
Number of pages12
ISSN0270-7306
DOIs
Publication statusPublished - 1. Jun 2008

Keywords

  • 3T3-L1 Cells
  • Adipocytes
  • Adipogenesis
  • Animals
  • Carrier Proteins
  • Cyclic AMP
  • Cyclic AMP Response Element-Binding Protein
  • Cyclic AMP-Dependent Protein Kinases
  • Guanine Nucleotide Exchange Factors
  • Insulin-Like Growth Factor I
  • Mice
  • rap GTP-Binding Proteins
  • rap1 GTP-Binding Proteins
  • rho-Associated Kinases

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