Abstract
To date, the only known role of the spliced form of X-box–binding protein-1 (XBP-1s) in metabolic processes has been its ability to act as a transcription factor that regulates the expression of genes that increase the endoplasmic reticulum (ER) folding capacity, thereby improving insulin sensitivity. Here we show that XBP-1s interacts with the Forkhead box O1 (FoxO1) transcription factor and directs it toward proteasome-mediated degradation. Given this new insight, we tested modest hepatic overexpression of XBP-1s in vivo in mouse models of insulin deficiency or insulin resistance and found it improved serum glucose concentrations, even without improving insulin signaling or ER folding capacity. The notion that XBP-1s can act independently of its role in the ER stress response is further supported by our finding that in the severely insulin resistant ob/ob mouse strain a DNA-binding–defective mutant of XBP-1s, which does not have the ability to increase ER folding capacity, is still capable of reducing serum glucose concentrations and increasing glucose tolerance. Our results thus provide the first evidence to our knowledge that XBP-1s, through its interaction with FoxO1, can bypass hepatic insulin resistance independent of its effects on ER folding capacity, suggesting a new therapeutic approach for the treatment of type 2 diabetes.
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Acknowledgements
We thank members of the Ozcan laboratory for their help during the execution of the experiments. We thank L. Glimcher (Harvard School of Public Health) for providing us with the Xbp1flox/flox mouse strain. We are grateful to D. Accili (Columbia University) for providing us with various FoxO1 adenoviruses and to R. Kahn (Joslin Diabetes Center) for his permission to use LIRKO mice in our studies. We thank J. Majzoub (Harvard Medical School) for providing us with the mammalian two-hybrid system and R. King (Harvard Medical School) for providing us with a ubiquitin-expressing plasmid. We thank M. Birnbaum (University of Pennsylvania) for providing us with Akt1/2 double-knockout cells. This study was supported by junior faculty start-up funds provided to U.O. by Children's Hospital Boston, an RO1 grant (R01DK081009) provided to U.O. by the US National Institutes of Health, and the Timothy Murphy funds provided to the Division of Endocrinology, Children's Hospital Boston.
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Y.Z. came up with the hypothesis, designed and performed the experiments, analyzed the data and wrote the manuscript. Justin Lee, C.M.R., C.S., S.W.P., J.C., Jaemin Lee and S.J.F. performed the experiments. M.F.W. provided liver specific IRS1/2 double-knockout mice. S.B.B. provided LIRKO mice and performed experiments. U.O. came up with the hypothesis, designed and performed the experiments, analyzed the data and wrote the manuscript.
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Zhou, Y., Lee, J., Reno, C. et al. Regulation of glucose homeostasis through a XBP-1–FoxO1 interaction. Nat Med 17, 356–365 (2011). https://doi.org/10.1038/nm.2293
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DOI: https://doi.org/10.1038/nm.2293
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