Abstract
Saturated free fatty acid (FFA) is a major source of metabolic stress that activates the c-Jun NH(2)-terminal kinase (JNK). This FFA-stimulated JNK pathway is relevant to hallmarks of metabolic syndrome, including insulin resistance. Here we used gene ablation studies in mice to demonstrate a central role for mixed-lineage protein kinases (MLK) in this signaling pathway. Saturated FFA causes protein kinase C (PKC)-dependent activation of MLK3 that subsequently causes increased JNK activity by a mechanism that requires the MAP kinase kinases MKK4 and MKK7. Loss of PKC, MLK3, MKK4, or MKK7 expression prevents FFA-stimulated JNK activation. Together, these data establish a signaling pathway that mediates effects of metabolic stress on insulin resistance.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Embryo, Mammalian / cytology
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Embryo, Mammalian / metabolism
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Fatty Acids, Nonesterified / pharmacology*
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Insulin Receptor Substrate Proteins
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JNK Mitogen-Activated Protein Kinases / metabolism
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MAP Kinase Kinase 3 / genetics
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MAP Kinase Kinase 3 / physiology
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MAP Kinase Kinase 7 / genetics
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MAP Kinase Kinase 7 / physiology
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MAP Kinase Kinase Kinases / genetics
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MAP Kinase Kinase Kinases / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mitogen-Activated Protein Kinase Kinase Kinase 11
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Phosphoproteins
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Protein Kinase C / metabolism
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Signal Transduction*
Substances
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Fatty Acids, Nonesterified
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Insulin Receptor Substrate Proteins
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Irs1 protein, mouse
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Phosphoproteins
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Protein Kinase C
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JNK Mitogen-Activated Protein Kinases
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MAP Kinase Kinase Kinases
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Map3k9 protein, mouse
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MAP Kinase Kinase 3
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MAP Kinase Kinase 7
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Map2k7 protein, mouse