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

Mol Cell Biol. 2008 Jun;28(11):3804-16. doi: 10.1128/MCB.00709-07. Epub 2008 Apr 7.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipocytes / cytology
  • Adipocytes / drug effects
  • Adipocytes / metabolism*
  • Adipogenesis*
  • Animals
  • Carrier Proteins / metabolism*
  • Cyclic AMP / metabolism*
  • Cyclic AMP / pharmacology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Insulin-Like Growth Factor I / metabolism
  • Insulin-Like Growth Factor I / pharmacology
  • Mice
  • rap GTP-Binding Proteins / genetics
  • rap GTP-Binding Proteins / metabolism
  • rap1 GTP-Binding Proteins / genetics
  • rap1 GTP-Binding Proteins / metabolism
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism

Substances

  • Carrier Proteins
  • Cyclic AMP Response Element-Binding Protein
  • Epac protein, mouse
  • Guanine Nucleotide Exchange Factors
  • Rapgef4 protein, mouse
  • Insulin-Like Growth Factor I
  • Cyclic AMP
  • rho-Associated Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • Rap2a protein, mouse
  • rap GTP-Binding Proteins
  • rap1 GTP-Binding Proteins