Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipose Tissue, Brown / cytology
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Adipose Tissue, Brown / drug effects*
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Adipose Tissue, Brown / embryology
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Animals
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Body Temperature Regulation / physiology
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Calcium-Calmodulin-Dependent Protein Kinases / physiology*
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Cell Cycle
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Cell Nucleus / metabolism
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Cells, Cultured
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Cytosol / metabolism
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Enzyme Activation
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Enzyme Induction
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Fatty Acid Synthases / biosynthesis
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Fatty Acid Synthases / genetics
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Insulin / pharmacology*
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Insulin-Like Growth Factor I / pharmacology*
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase 1 / physiology*
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinase Kinases*
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Mitogen-Activated Protein Kinases*
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Proliferating Cell Nuclear Antigen / analysis
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Protein Serine-Threonine Kinases / physiology
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Protein-Tyrosine Kinases / physiology
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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Rats
Substances
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Insulin
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Proliferating Cell Nuclear Antigen
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RNA, Messenger
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Insulin-Like Growth Factor I
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Fatty Acid Synthases
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Protein-Tyrosine Kinases
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Protein Serine-Threonine Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 1
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Mitogen-Activated Protein Kinase Kinases