Novel suppression mechanism operating in early phase of adipogenesis by positive feedback loop for enhancement of cyclooxygenase-2 expression through prostaglandin F2α receptor mediated activation of MEK/ERK-CREB cascade

FEBS J. 2011 Aug;278(16):2901-12. doi: 10.1111/j.1742-4658.2011.08213.x. Epub 2011 Jun 28.


Prostaglandin (PG) F(2α) suppresses adipocyte differentiation by inhibiting the function of peroxisome proliferator-activated receptor γ. In this study, we identified a novel suppression mechanism, operating in the early phase of adipogenesis, that increased the production of anti-adipogenic PGF(2α) and PGE(2) by enhancing cyclooxygenase (COX) 2 expression through the PGF(2α) -activated FP receptor/extracellular-signal-regulated kinase (ERK)/cyclic AMP response element binding protein (CREB) cascade. COX-2 expression was enhanced with a peak at 1 h for the mRNA level and at 3 h for the protein level after the addition of Fluprostenol, an FP receptor agonist. The Fluprostenol-derived elevation of COX-2 expression was suppressed by the co-treatment with an FP receptor antagonist, AL8810, with a mitogen-activated protein kinase (MEK; ERK kinase) inhibitor, PD98059. ERK was phosphorylated within 10 min after the addition of Fluprostenol, and its phosphorylation was inhibited by the co-treatment with AL8810 or PD98059. Moreover, FP receptor mediated activation of the MEK/ERK cascade and COX-2 expression increased the production of PGF(2α) and PGE(2) . An FP receptor antagonist and each inhibitor for MEK and COX-2 suppressed the PGF(2α) -derived induction of synthesis of these PGs. Furthermore, promoter-luciferase and chromatin immunoprecipitation assays demonstrated that PGF(2α) -derived COX-2 expression was activated through binding of CREB to the promoter region of the COX-2 gene in 3T3-L1 cells. These results indicate that PGF(2α) suppresses the progression of the early phase of adipogenesis by enhancing the binding of CREB to the COX-2 promoter via FP receptor activated MEK/ERK cascade. Thus, PGF(2α) forms a positive feedback loop that coordinately suppresses the early phase of adipogenesis through the increased production of anti-adipogenic PGF(2α) and PGE(2) .

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3-L1 Cells
  • Adipogenesis / drug effects*
  • Animals
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclooxygenase 2 / genetics*
  • Dinoprost / biosynthesis
  • Dinoprostone / biosynthesis
  • Extracellular Signal-Regulated MAP Kinases / physiology*
  • Feedback
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase Kinases / metabolism*
  • PPAR gamma / metabolism
  • Prostaglandins F, Synthetic / pharmacology
  • Receptors, Prostaglandin / physiology*
  • Signal Transduction / physiology


  • Cyclic AMP Response Element-Binding Protein
  • PPAR gamma
  • Prostaglandins F, Synthetic
  • Receptors, Prostaglandin
  • prostaglandin F2alpha receptor
  • fluprostenol
  • Dinoprost
  • Cyclooxygenase 2
  • Extracellular Signal-Regulated MAP Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase Kinases
  • Dinoprostone