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Yin Yang 1 deficiency in skeletal muscle protects against rapamycin-induced diabetic-like symptoms through activation of insulin/IGF signaling.
Cell Metab. 2012 Apr 4; 15(4):505-17
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12 Jun 2012
New Finding, Novel Drug Target
DOI: 10.3410/f.716547845.791952837
This study provides new insights into the yin and yang of rapamycin treatment. Blättler et al. identify the molecular mechanisms that may underlie the unexpected development of insulin resistance and pro-diabetic symptoms in some patients taking rapamycin. Rapamycin is a drug used as an immunosuppressant in organ transplant recipients and is in clinical trials for cancer treatment. It has also recently been shown to extend lifespan in rodent models. Blättler et al. show that the transcription factor Yin Yang 1 (YY1) provides an important mechanistic link between mammalian target of rapamycin (mTOR) activity and insulin resistance with rapamycin treatment.
The beneficial effects of rapamycin are largely attributed to the inhibition of mTOR, but it was not clear how inhibition of mTOR caused diabetes-like symptoms. This was especially true because a substrate of mTOR, S6k, directly inhibits insulin signaling through insulin receptor substrate 1. Thus, rapamycin inhibition of mTOR would be expected to reduce S6k activity and promote insulin signaling. The study by Blättler et al. builds on earlier work from this group demonstrating that the YY1 transcription factor is one of mTOR’s many downstream targets {1}. In this study they use YY1 skeletal muscle-specific knockout mice to demonstrate that YY1 inhibits insulin-responsive genes by forming a complex that is recruited to their promoters and results in epigenetic modification to turn down expression. Phosphorylation of YY1 by mTOR inhibits this complex formation, thereby releasing the inhibition of insulin signaling. Thus, inhibition of mTOR activity by rapamycin results in the YY1 complex inhibition of insulin signaling and impaired skeletal muscle glucose uptake. This study provides several important insights. First, it demonstrates that skeletal muscle is an important target of rapamycin and that this interaction is sufficient to induce diabetes-like symptoms. Second, the molecular mechanisms contributing to insulin resistance with rapamycin treatment reveal several potential therapeutic targets for reducing this negative side effect of rapamycin treatment. Unraveling this pathway is an important step toward identifying why only a subset of patients develop these symptoms.
References
1.
mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex.
Nature. 2007 Nov 29; 450(7170): 736-40
PMID: 18046414
DOI: 10.1038/nature06322
Disclosures
None declared
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Marcinek D and Kruse S: F1000Prime Recommendation of [Blättler SM et al., Cell Metab 2012, 15(4):505-17]. In F1000Prime, 12 Jun 2012; DOI: 10.3410/f.716547845.791952837. F1000Prime.com/716547845#eval791952837
F1000Prime Recommendations, Dissents and Comments for [Blättler SM et al., Cell Metab 2012, 15(4):505-17]. In F1000Prime, 20 Jun 2013; F1000Prime.com/716547845
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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.
DOI: 10.1016/j.cmet.2012.03.008
PMID: 22482732
