Abstract
Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk. We show here that the catalytic activity of Vav2, a Rho GTPase activator, modulates the signaling output of the IGF1- and insulin-stimulated phosphatidylinositol 3-kinase pathway in that tissue. Consistent with this, mice bearing a Vav2 protein with decreased catalytic activity exhibit reduced muscle mass, lack of proper insulin responsiveness and, at much later times, a metabolic syndrome-like condition. Conversely, mice expressing a catalytically hyperactive Vav2 develop muscle hypertrophy and increased insulin responsiveness. Of note, while hypoactive Vav2 predisposes to, hyperactive Vav2 protects against high fat diet-induced metabolic imbalance. These data unveil a regulatory layer affecting the signaling output of insulin family factors in muscle.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adipocytes, White / drug effects
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Adipocytes, White / metabolism
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Adipose Tissue, Brown / metabolism
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Animals
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Biocatalysis* / drug effects
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Body Composition / drug effects
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Body Weight / drug effects
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Cell Line
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Cell Size / drug effects
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Genotype
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Glucose / pharmacology
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Homeostasis* / drug effects
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Insulin / metabolism
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Insulin-Like Growth Factor I / metabolism
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Metabolism*
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Mice, Inbred C57BL
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Mice, Knockout
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Muscle Cells / cytology
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Muscle Cells / drug effects
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Muscle Cells / metabolism
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / growth & development*
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Muscle, Skeletal / metabolism*
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Organ Size / drug effects
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-vav / metabolism*
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Signal Transduction* / drug effects
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Up-Regulation / drug effects
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rac1 GTP-Binding Protein / metabolism
Substances
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Insulin
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Proto-Oncogene Proteins c-vav
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Vav2 protein, mouse
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Insulin-Like Growth Factor I
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Proto-Oncogene Proteins c-akt
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rac1 GTP-Binding Protein
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Glucose