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Inhibition of p38MAPK Increases Adipogenesis From Embryonic to Adult Stages

From the Institut National de la Santé et de al Recherche Médicale (INSERM) U568, Nice, France; and Université de Nice Sophia Antipolis, Faculte de Médicine, Nice, France

Address correspondence and reprint requests to Frédéric Bost or Bernard Binétruy, Faculte de Medecine, INSERM U568, Avenue de Valombrose, Nice 06107, France. E-mail: bost{at}unice.fr or bernard.binetruy{at}medecine.univ-mrs.fr

Key Words: C/EBPß, CCAAT/enhancer-binding protein ß • ERK, extracellular signal–regulated kinase • JNK, c-Jun amino-terminal kinase • MAPK, mitogen-activated protein kinase • MEF, mouse embryonic fibroblast • NFAT, nuclear factor of activated T-cell • PPAR, peroxisome proliferator–activated receptor • PPRE, PPAR responsive element • PPRE-luc, PPRE-luciferase • TZD, thiazolidinedione

Formation of new adipocytes from precursor cells contributes to adipose tissue expansion and obesity. In this study, we asked whether p38 mitogen-activated protein kinase (MAPK) pathway regulates normal and pathological adipogenesis. In both dietary and genetically (ob/ob) obese mice, adipose tissues displayed a marked decrease in p38MAPK activity compared with the same tissues from lean mice. Furthermore, p38MAPK activity was significantly higher in preadipocytes than in adipocytes, suggesting that p38MAPK activity decreases during adipocyte differentiation. In agreement with an inhibitory role of p38MAPK in this process, we found that in vitro inhibition of p38MAPK, with the specific inhibitor PD169316, increased the expression of adipocyte markers in several cellular models, from embryonic to adult stages. Importantly, the expression of adipocyte markers was higher in p38MAPK knockout cells than in their wild-type counterparts. Phosphorylation of C/EBPß, which enhances its transcriptional activity, is increased after p38MAPK inhibition. Finally, either inhibition or disruption of p38MAPK increased peroxisome proliferator–activated receptor (PPAR) expression and transactivation. Rescue of p38MAPK in knockout cells reduced PPAR activity to the low basal level of wild-type cells. We demonstrate here, by using multipronged approaches involving p38 chemical inhibitor and p38MAPK knockout cells, that p38MAPK plays a negative role in adipogenesis via inhibition of C/EBPß and PPAR transcriptional activities.

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