The DOI matches its Crossref record; 58 of the 58 references it cites were found in a registry or an index.
FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases
Open accessAbstract
Insulin resistance and metabolic syndrome are rapidly expanding public health problems. Acting through the PI3K/Akt pathway, insulin and insulin-like growth factor-1 (IGF-1) inactivate FoxO transcription factors, a class of highly conserved proteins important in numerous physiological functions. However, even as FoxO is a downstream target of insulin, FoxO factors also control upstream signaling elements governing insulin sensitivity and glucose metabolism. Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity. FoxO-activated Akt directly interacts with and phosphorylates FoxO, providing feedback inhibition. We reported previously that FoxO factors attenuate cardiomyocyte calcineurin (PP2B) activity. We now show that calcineurin forms a complex with Akt and inhibition of calcineurin enhances Akt phosphorylation. In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt–calcineurin interactions. Repression of Akt–PP2A/B interactions and phosphatase activities contributes, at least in part, to FoxO-dependent increases in Akt phosphorylation and kinase activity. Resveratrol, an activator of Sirt1, increases the transcriptional activity of FoxO1 and triggers Akt phosphorylation in heart. Importantly, FoxO-mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulin-triggered glucose uptake. Also, inactivation of the gene coding for FoxO3 enhances insulin-dependent Akt phosphorylation. Taken together, this study demonstrates that changes in FoxO activity have a dose-responsive repressive effect on insulin signaling in cardiomyocytes through inhibition of protein phosphatases, which leads to altered Akt activation, reduced insulin sensitivity, and impaired glucose metabolism.
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Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex
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Resveratrol improves health and survival of mice on a high-calorie diet
Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., et al. (2006) · Nature · doi:10.1038/nature05354 · Cited by 4,290
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Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase
Brunet, A., Sweeney, L. B., Sturgill, J. F., Chua, K. F., Greer, P. L., Lin, Y., Tran, H., Ross, S. E., Mostoslavsky, R., Cohen, H. Y., et al. (2004) · Science · doi:10.1126/science.1094637 · Cited by 3,239
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Cited by
Metabolic stress–induced activation of FoxO1 triggers diabetic cardiomyopathy in mice
Battiprolu, P. K., Hojayev, B., Jiang, N., Wang, Z. V., Luo, X., Iglewski, M., Shelton, J. M., Gerard, R. D., Rothermel, B. A., Gillette, T. G., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60329 · Cited by 345
Self-citationAMP-activated protein kinase adapts rRNA synthesis to cellular energy supply
Hoppe, S., Bierhoff, H., Cado, I., Weber, A., Tiebe, M., Grummt, I., & Voit, R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909873106 · Cited by 225
Clk2 and B56β mediate insulin-regulated assembly of the PP2A phosphatase holoenzyme complex on Akt
Rodgers, J. T., Vogel, R. O., & Puigserver, P. (2011) · Molecular Cell · doi:10.1016/j.molcel.2011.02.007 · Cited by 99
Diabetic cardiomyopathy and metabolic remodeling of the heart
Battiprolu, P. K., Lopez-Crisosto, C., Wang, Z. V., Nemchenko, A., Lavandero, S., & Hill, J. A. (2013) · Life Sciences · doi:10.1016/j.lfs.2012.10.011 · Cited by 91
Self-citationSaturated free fatty acids induce cholangiocyte lipoapoptosis
Natarajan, S. K., Ingham, S. A., Mohr, A. M., Wehrkamp, C. J., Ray, A., Roy, S., Cazanave, S. C., Phillippi, M. A., & Mott, J. L. (2014) · Hepatology · doi:10.1002/hep.27175 · Cited by 62
Metadata
- Authors
- Ni, Y. G., Wang, N., Cao, D. J., Sachan, N., Morris, D. J., Gerard, R. D., Kuro-o, M., Rothermel, B. A., & Hill, J. A.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2007-12-18
- Volume
- 104
- Issue
- 51
- Pages
- 20517-20522
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W1987003603
- Cited by
- 279
- References
- 58
- FWCI
- 6.94
- Type
- journal article
- Language
- en
- Open access
- green
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