title: Peroxisome proliferator-activated receptor-γ activation enhances insulin-stimulated glucose disposal by reducing ped/pea-15 gene expression in skeletal muscle cells: evidence for involvement of activator protein-1.
abstract: The gene network responsible for inflammation-induced insulin resistance remains enigmatic. In this study, we show that, in L6 cells, rosiglitazone- as well as pioglitazone-dependent activation of peroxisome proliferator-activated receptor-γ (PPARγ) represses transcription of the ped/pea-15 gene, whose increased activity impairs glucose tolerance in mice and humans. Rosiglitazone enhanced insulin-induced glucose uptake in L6 cells expressing the endogenous ped/pea-15 gene but not in cells expressing ped/pea-15 under the control of an exogenous promoter. The ability of PPARγ to affect ped/pea-15 expression was also lost in cells and in C57BL/6J transgenic mice expressing ped/pea-15 under the control of an exogenous promoter, suggesting that ped/pea-15 repression may contribute to rosiglitazone action on glucose disposal. Indeed, high fat diet mice showed insulin resistance and increased ped/pea-15 levels, although these effects were reduced by rosiglitazone treatment. Both supershift and ChIP assays revealed the presence of the AP-1 component c-JUN at the PED/PEA-15 promoter upon 12-O-tetradecanoylphorbol-13-acetate stimulation of the cells. In these experiments, rosiglitazone treatment reduced c-JUN presence at the PED/PEA-15 promoter. This effect was not associated with a decrease in c-JUN expression. In addition, c-jun silencing in L6 cells lowered ped/pea-15 expression and caused nonresponsiveness to rosiglitazone, although c-jun overexpression enhanced the binding to the ped/pea-15 promoter and blocked the rosiglitazone effect. These results indicate that PPARγ regulates ped/pea-15 transcription by inhibiting c-JUN binding at the ped/pea-15 promoter. Thus, ped/pea-15 is downstream of a major PPARγ-regulated inflammatory network. Repression of ped/pea-15 transcription might contribute to the PPARγ regulation of muscle sensitivity to insulin.
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università di Napoli "Federico II", Consiglio Nazionale delle Ricerche, 80131 Naples, Italy. pungaro@ieos.cnr.it
authors.forename: Paola
authors.initials: P
authors.lastname: Ungaro
authors.forename: Paola
authors.initials: P
authors.lastname: Mirra
authors.forename: Francesco
authors.initials: F
authors.lastname: Oriente
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nigro
authors.forename: Marco
authors.initials: M
authors.lastname: Ciccarelli
authors.forename: Viviana
authors.initials: V
authors.lastname: Vastolo
authors.forename: Michele
authors.initials: M
authors.lastname: Longo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Perruolo
authors.forename: Rosa
authors.initials: R
authors.lastname: Spinelli
authors.forename: Pietro
authors.initials: P
authors.lastname: Formisano
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D059305:Diet, High-Fat; D005247:Feeding Behavior / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology; D047495:PPAR gamma / Q000378:metabolism*; D010750:Phosphoproteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D051381:Rats; D000077154:Rosiglitazone; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D045162:Thiazolidinediones / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D051017:Apoptosis Regulatory Proteins; D007328:Insulin; D047495:PPAR gamma; C490444:Pea15 protein, mouse; D010750:Phosphoproteins; D045162:Thiazolidinediones; D018808:Transcription Factor AP-1; D000077154:Rosiglitazone; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate