Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling

Sharon M. Blättler, John T. Cunningham, Francisco Verdeguer, Helen Chim, Wilhelm Haas, Huifei Liu, Klaas Romanino, Markus A. Rüegg, Steven P. Gygi, Yang Shi, Pere Puigserver

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)505-517
Number of pages13
JournalCell Metabolism
Volume15
Issue number4
DOIs
StatePublished - Apr 4 2012
Externally publishedYes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Physiology

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