Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is required for the conversion of pre-adipocytes. However, the mechanism underlying activation of PPAR-gamma is unclear. Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-gamma. Hormonal induction of adipogenesis was blocked by a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), by a protein kinase A (PKA) inhibitor (H89), and by a Rap1 inhibitor (GGTI-298). Transcriptional activity of PPAR-gamma was markedly enhanced by 3-isobutyl-1-methylxanthine (IBMX), but not insulin and dexamethasone. In addition, IBMX-induced PPAR-gamma transcriptional activity was blocked by PI3K/Akt, PKA, or Rap1 inhibitors. 8-(4-Chlorophenylthio)-2'-O-methyl-cAMP (8-pCPT-2'-O-Me-cAMP) which is a specific agonist for exchanger protein directly activated by cAMP (Epac) significantly induced the activation of Akt. Furthermore, knock-down of Akt1 markedly attenuated PPAR-gamma transcriptional activity. These results indicate that both PKA and Akt signaling pathways are required for transcriptional activation of PPAR-gamma, suggesting post-translational activation of PPAR-gamma might be critical step for adipogenic gene expression. (C) 2010 Elsevier Inc. All rights reserved.