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/

Insulin-like growth factor I (IGF-I)/insulin induced cytosolic p42/p44 mitogen-activated protein kinase (MAPK) activation in a time-dependen t manner in fetal brown adipocytes, reaching a maximum at 5 min. Concu rrently, nuclear p42/p44 MAPKs were also activated by IGF-I and insuli n, This cytosolic and nuclear MAPK activation was totally prevented by pretreatment with the MAPK kinase (MEK1) inhibitor, PD98059. These re sults indicate that MEK mediates the IGF-I/insulin-induced p42/p44 MAP K activation. IGF-I and insulin also increased the number of cells in the S+G(2)/M phases of the cell cycle, PCNA levels, and DNA synthesis at 24 h, This IGF-I/insulin-induced proliferation was completely blunt ed by the presence of MEK1 inhibitor. In contrast, inhibition of MEK1 potentiated the IGF-I-induced uncoupling protein (UCP-1) and the insul in-induced fatty acid synthase mRNAs expression after short and long-t erm 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 p 42/p44 MAPKs are essential intermediates for the IGF-I/insulin-induced mitogenesis, but may have a negative role in the regulation of adipoc ytic and thermogenic differentiation in brown adipocytes.