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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 p38MAPKa knockout cells than in their wild-type counterparts. Phosphorylation of C/EBPβ, which enhances its transcriptional activity, is increased after p38MAPK inhibition. Finally, either inhibition or disruption of p38MAPK increased peroxisome proliferator-activated receptor (PPAR)γ expression and transactivation. Rescue of p38MAPK in knockout cells reduced PPARγ activity to the low basal level of wild-type cells. We demonstrate here, by using multipronged approaches involving p38 chemical inhibitor and p38MAPKα knockout cells, that p38MAPK plays a negative role in adipogenesis via inhibition of C/EBPβ and PPARγ transcriptional activities., Intracellular mitogen-activated protein kinase (MAPK) signaling pathways play a pivotal role in many essential cellular processes, such as proliferation, inflammation, and differentiation. The MAPK family comprises three groups: extracellular signal-regulated [...]

Hyperplasia of adipose tissue is critical for the development of obesity, but molecular mechanisms governing normal or pathological recruitment of new adipocytes remain unclear. The extracellular signal-regulated kinase (ERK) pathway plays a pivotal role in many essential cellular functions, such as proliferation and differentiation. Using ERK[1.sup.-/-] mice, we investigated the role of this isoform in adipose tissue development. Mice lacking ERK1 have decreased adiposity and fewer adipocytes than wild-type animals. Furthermore, ERK[1.sub.-/-] mice challenged with high-fat diet are resistant to obesity, are protected from insulin resistance, and have a higher postprandial metabolic rate. To get insights into cellular mechanisms implicated in reduced adiposity in ERK[1.sup.-/-] animals, we analyzed adipocyte differentiation in ERK1-/- cells. Compared with wild-type control cells, mouse embryo fibroblasts and cultures of adult preadipocytes isolated from ERK[1.sup.-/-] adult animals exhibit impaired adipogenesis. An inhibitor of the ERK pathway does not affect the residual adipogenesis of the ERK[1.sup.-/-] cells, suggesting that ERK2 is not implicated in adipocyte differentiation. Our results clearly link ERK1 to the regulation of adipocyte differentiation, adiposity, and high-fat diet-induced obesity. This suggests that a therapeutic approach of obesity targeting specifically the ERK1 isoform and not ERK2 would be of particular interest., Obesity represents a major health hazard and is a high-risk factor for type 2 diabetes and cardiovascular diseases. One of the main functions of adipocytes is to store surplus calories [...]