Abstract
Rapamycin and its derivatives are mTOR inhibitors used in tissue transplantation and cancer therapy. A percentage of patients treated with these inhibitors develop diabetic-like symptoms, but the molecular mechanisms are unknown. We show here that chronic rapamycin treatment in mice led to insulin resistance with suppression of insulin/IGF signaling and genes associated within this pathway, such as Igf1-2, Irs1-2, and Akt1-3. Importantly, skeletal muscle-specific YY1 knockout mice were protected from rapamycin-induced diabetic-like symptoms. This protection was caused by hyperactivation of insulin/IGF signaling with increased gene expression in this cascade that, in contrast to wild-type mice, was not suppressed by rapamycin. Mechanistically, rapamycin induced YY1 dephosphorylation and recruitment to promoters of insulin/IGF genes, which promoted interaction with the polycomb protein-2 corepressor. This was associated with H3K27 trimethylation leading to decreased gene expression and insulin signaling. These results have implications for rapamycin action in human diseases and biological processes such as longevity.
Copyright © 2012 Elsevier Inc. All rights reserved.
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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Diabetes Mellitus, Experimental / metabolism
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Diabetes Mellitus, Experimental / prevention & control*
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Enhancer of Zeste Homolog 2 Protein
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Gene Expression Regulation / drug effects
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Histone-Lysine N-Methyltransferase / metabolism
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Histones / metabolism
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Humans
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Insulin / metabolism*
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Insulin Resistance / genetics
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Insulin-Like Growth Factor I / metabolism*
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Lipid Metabolism / drug effects
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Liver / drug effects
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Liver / metabolism
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Lysine / metabolism
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Methylation / drug effects
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Mice
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Mice, Knockout
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Models, Biological
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Muscle, Skeletal / drug effects
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Muscle, Skeletal / metabolism*
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Organ Specificity / drug effects
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Organ Specificity / genetics
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Polycomb Repressive Complex 2
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Polycomb-Group Proteins
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Promoter Regions, Genetic / genetics
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Protein Binding / drug effects
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Repressor Proteins / metabolism
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Signal Transduction / drug effects*
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Signal Transduction / genetics
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Sirolimus / pharmacology*
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YY1 Transcription Factor / deficiency*
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YY1 Transcription Factor / metabolism
Substances
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Histones
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Insulin
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Polycomb-Group Proteins
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Repressor Proteins
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YY1 Transcription Factor
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Yy1 protein, mouse
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Insulin-Like Growth Factor I
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Enhancer of Zeste Homolog 2 Protein
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Ezh2 protein, mouse
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Histone-Lysine N-Methyltransferase
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Polycomb Repressive Complex 2
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Lysine
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Sirolimus