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Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner

Nature Medicine volume 17, pages 961967 (2011) | Download Citation

Abstract

Transcription factor FoxO1 promotes hepatic glucose production. Genetic inhibition of FoxO1 function prevents diabetes in experimental animal models, providing impetus to identify pharmacological approaches to modulate this function. Altered Notch signaling is evident in tumorigenesis, and Notch antagonists are in clinical testing for application in cancer. Here we report that FoxO1 and Notch coordinately regulate hepatic glucose metabolism. Combined haploinsufficiency of FoxO1 and Notch1 markedly raises insulin sensitivity in diet-induced insulin resistance, as does liver-specific knockout of the Notch transcriptional effector Rbp-Jκ. Conversely, Notch1 gain-of-function promotes insulin resistance in a FoxO1-dependent manner and induces glucose-6-phosphatase expression. Pharmacological blockade of Notch signaling with γ-secretase inhibitors raises insulin sensitivity after in vivo administration in lean mice and in obese, insulin-resistant mice. The data identify a heretofore unknown metabolic function of Notch and suggest that Notch inhibition is beneficial in diabetes treatment, in part by helping to offset excessive FoxO1-driven hepatic glucose production.

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Acknowledgements

This work was supported by US National Institutes of Health grants DK57539 (D.A.), DK084583 (U.B.P.), DK63608 (Columbia Diabetes and Endocrinology Research Center), HL062454 (J.K.) and DK76169 (Yale Mouse Metabolic Phenotyping Center). We thank D. Schmoll (Sanofi-Aventis) for the G6pc-luciferase constructs, members of the Accili, Kitajewski and Shulman laboratories for insightful discussion of the data, and A. Flete, T. Kolar and T. Lu for technical support.

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Affiliations

  1. Department of Medicine, Columbia University, New York, New York, USA.

    • Utpal B Pajvani
    •  & Domenico Accili
  2. Department of Pathology, Columbia University, New York, New York, USA.

    • Carrie J Shawber
    •  & Jan Kitajewski
  3. Department of Obstetrics and Gynecology, Columbia University, New York, New York, USA.

    • Carrie J Shawber
    •  & Jan Kitajewski
  4. Department of Internal Medicine, Yale University, New Haven, Connecticut.

    • Varman T Samuel
    • , Andreas L Birkenfeld
    •  & Gerald I Shulman

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Contributions

U.B.P. designed and performed experiments, analyzed data and wrote the manuscript. C.J.S., A.L.B. and V.T.S. performed experiments and analyzed data. G.I.S., J.K. and D.A. designed the studies, analyzed the data and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Domenico Accili.

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DOI

https://doi.org/10.1038/nm.2378

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