title: 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.
abstract: 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) .
authors.affiliation: Laboratory of Biodefense and Regulation, Osaka University of Pharmaceutical Sciences, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Ueno
authors.forename: Ko
authors.initials: K
authors.lastname: Fujimori
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis / Q000187:drug effects*; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics*; D015237:Dinoprost / Q000096:biosynthesis; D015232:Dinoprostone / Q000096:biosynthesis; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005246:Feedback; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D011461:Prostaglandins F, Synthetic / Q000494:pharmacology; D011982:Receptors, Prostaglandin / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D047495:PPAR gamma; D011461:Prostaglandins F, Synthetic; D011982:Receptors, Prostaglandin; C034671:prostaglandin F2alpha receptor; C006326:fluprostenol; D015237:Dinoprost; D051546:Cyclooxygenase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases; D015232:Dinoprostone