MITOGEN-ACTIVATED PROTEIN-KINASE ACTIVATION IS NOT NECESSARY FOR, BUTANTAGONIZES, 3T3-L1 ADIPOCYTIC DIFFERENTIATION

In 3T3-L1 fibroblasts, Ras proteins mediate both insulin-induced diffe rentiation to adipocytes and its activation of cytosolic serine/threon ine kinases, including Raf-1 kinase, mitogen-activated protein kinase (MAPK), and Rsk. Here, we report that insulin-and Ras-induced activati on of MAPK is not required for the differentiation process and in fact antagonizes it, The treatment of 3T3-L1 preadipocytes with MEK-specif ic inhibitor PD98059 blocked insulin- and Ras-induced MAPK activation but had no effect on or slightly enhanced adipocytic differentiation. Tumor necrosis factor alpha (TNF-alpha), an inhibitor of insulin stimu lated adipogenesis, activated MAPK in 3T3-L1 cells. PD98059 treatment blocked MAPK activation by TNF-alpha and reversed the blockade of adip ogenesis mediated bg low (1 ng/ml) TNF-alpha concentrations. 3T3-L1 tr ansfectants containing hyperactivated MEK1 or overexpressed MAPK displ ayed impaired adipocytic differentiation, PD98059 treatment also rever sed the blockade of differentiation in MEK1 transfectants. These resul ts indicate that MAPK does not promote but can contribute to inhibitio n of the process of adipocytic differentiation of 3T3-L1 cells.