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p42/p44 Mitogen-Activated Protein Kinases Activation Is Required for the Insulin-Like Growth Factor-I/Insulin Induced Proliferation, but Inhibits Differentiation, in Rat Fetal Brown Adipocytes

Departamento de Bioquímica y Biología Molecular II (A.P., A.V., M.B.) Instituto de Bioquímica (Centro Mixto del Consejo Superior de Investigaciones Científicas y de la Universidad Complutense) and Centro de Citometría de Flujo y Microscopía Confocal (A.M.A.) U.C.M.; Facultad de Farmacia Universidad Complutense Ciudad Universitaria, 28040 Madrid, Spain

Insulin-like growth factor I (IGF-I)/insulin induced cytosolic p42/p44 mitogen-activated protein kinase (MAPK) activation in a time-dependent manner in fetal brown adipocytes, reaching a maximum at 5 min. Concurrently, nuclear p42/p44 MAPKs were also activated by IGF-I and insulin. This cytosolic and nuclear MAPK activation was totally prevented by pretreatment with the MAPK kinase (MEK1) inhibitor, PD98059. These results indicate that MEK mediates the IGF-I/insulin-induced p42/p44 MAPK activation. IGF-I and insulin also increased the number of cells in the S+G₂/M phases of the cell cycle, PCNA levels, and DNA synthesis at 24 h. This IGF-I/insulin-induced proliferation was completely blunted by the presence of MEK1 inhibitor. In contrast, inhibition of MEK1 potentiated the IGF-I-induced uncoupling protein (UCP-1) and the insulin-induced fatty acid synthase mRNAs expression after short and long-term treatments. Moreover, transient expression of a transfected active MEK construct (R4F) decreased IGF-I-induced UCP-1 and insulin-induced fatty acid synthase mRNA expression. These results demonstrate that p42/p44 MAPKs are essential intermediates for the IGF-I/insulin-induced mitogenesis, but may have a negative role in the regulation of adipocytic and thermogenic differentiation in brown adipocytes.

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