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Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer

Nature Metabolism volume 1, pages 371–389 (2019)Cite this article

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Abstract

Obesity promotes the development of insulin resistance and increases the incidence of colitis-associated cancer (CAC), but whether a blunted insulin action specifically in intestinal epithelial cells (IECs) affects CAC is unknown. Here, we show that obesity impairs insulin sensitivity in IECs and that mice with IEC-specific inactivation of the insulin and IGF1 receptors exhibit enhanced CAC development as a consequence of impaired restoration of gut barrier function. Blunted insulin signalling retains the transcription factor FOXO1 in the nucleus to inhibit expression of Dsc3, thereby impairing desmosome formation and epithelial integrity. Both IEC-specific nuclear FoxO1ADA expression and IEC-specific Dsc3 inactivation recapitulate the impaired intestinal integrity and increased CAC burden. Spontaneous colonic tumour formation and compromised intestinal integrity are also observed upon IEC-specific coexpression of FoxO1ADA and a stable Myc variant, thus suggesting a molecular mechanism through which impaired insulin action and nuclear FOXO1 in IECs promotes CAC.

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Fig. 1: Diet-induced obesity impairs insulin action in cIECs.
Fig. 2: Genetic blunting of insulin action in IECs via IR/IGF1R deficiency promotes CAC by impaired restoration of the gut barrier.
Fig. 3: Insulin-regulated gene expression via FOXO1 increases CAC.
Fig. 4: Deregulated Dsc3 expression in insulin-resistant tumours.
Fig. 5: Compromised desmosome formation in CAC of Ir/Igf1rIEC-KO and FoxO1ADAIEC mice.
Fig. 6: IEC-specific DSC3 inactivation promotes CAC.
Fig. 7: Genetic FOXO1 and MYC overactivation in IECs synergistically regulate colon tumorigenesis.
Fig. 8: Proposed model of how insulin resistance and nuclear FoxO1 impair gut barrier function to promote CAC.

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Data availability

The authors declare that the data supporting the findings of this study are available within the article and its supplementary information files, or are available upon reasonable request to the authors. Microarray expression data for tumours of C57BL/6 NCD and C57BL/6 HFD mice are available at gene expression omnibus website (https://www.ncbi.nlm.nih.gov/geo/) with accession number GSE113303. Microarray expression data for tumours of FoxO1ADAFL and FoxO1ADAIEC mice are available with accession number GSE118639.

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Acknowledgements

A.L.O. was supported by the Cologne CECAD graduate school of ageing, the MPI for Metabolism research and received a ‘Köln Fortune’ grant from the medical faculty of the University of Cologne. FTW received grants from CECAD and from an associated project of the SFB670 funded by the DFG. C.M.W. was supported by CMMC grant of JCB. RCS received support from R01 CA129040. We are grateful for technical assistance from A. Lietzau, C. Baitzel, H. Krämer, P. Scholl, N. Spenrath, C. Schäfer, B. Hampel, A. Fromm and I.-F. Lee. We thank H. Fenselau for critical proofreading.

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  1. B. F. Belgardt

    Present address: German Diabetes Center (DDZ), Düsseldorf, Germany

Authors and Affiliations

  1. Max Planck Institute for Metabolism Research, Cologne, Germany

    A. L. Ostermann, C. M. Wunderlich, L. Schneiders, M. C. Vogt, M. A. Woeste, B. F. Belgardt, J. C. Brüning & F. T. Wunderlich

  2. Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Cologne, Germany

    A. L. Ostermann, C. M. Wunderlich, C. M. Niessen, B. Martiny, A. C. Schauss, P. Frommolt, J. C. Brüning & F. T. Wunderlich

  3. Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), Cologne, Germany

    A. L. Ostermann, C. M. Wunderlich, J. C. Brüning & F. T. Wunderlich

  4. Center for Molecular Medicine Cologne (CMMC), Cologne, Germany

    C. M. Wunderlich, C. M. Niessen & J. C. Brüning

  5. Institute for Molecular Medicine, University Hospital Mainz, Mainz, Germany

    A. Nikolaev & N. Hövelmeyer

  6. Department of Molecular and Medical Genetics, Oregon Health & Sciences University, Portland, OR, USA

    R. C. Sears

  7. Department of Dermatology, Charles C. Gates Regenerative Medicine and Stem Cell Biology Program, University of Colorado Denver, Aurora, CO, USA

    P. J. Koch

  8. Institute for Clinical Physiology, Charité, Berlin, Germany

    D. Günzel

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Contributions

A.L.O., C.M.W., L.S., M.A.W., A.N. and N.H. performed experiments and analysed data. M.C.V. and P.F. helped with microarray analysis. B.M. and A.S. helped with electron microscopy. D.G. performed Ussing chamber experiments. B.F.B., R.C.S. and P.J.K. provided conditional mouse strains. C.M.N., P.J.K. and J.C.B. provided expertise and essential materials. A.L.O. and F.T.W. designed experiments and wrote the paper.

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Correspondence to F. T. Wunderlich.

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Ostermann, A.L., Wunderlich, C.M., Schneiders, L. et al. Intestinal insulin/IGF1 signalling through FoxO1 regulates epithelial integrity and susceptibility to colon cancer. Nat Metab 1, 371–389 (2019). https://doi.org/10.1038/s42255-019-0037-8

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