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Abstract

Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5+ intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-δ) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-δ recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-δ-dependent manner. Notably, HFD- and agonist-activated PPAR-δ signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-δ signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-δ activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.

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Change history

  • 30 May 2018

    In Fig. 4e of this Article, the labels for 'Control' and 'HFD' were reversed; similarly, in Fig. 4f of this Article, the labels for 'V' and 'GW' were reversed. These errors have been corrected online.

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Primary accessions

Gene Expression Omnibus

Data deposits

RNA-sequencing data have been deposited in the Gene Expression Omnibus (GEO) database under accession number GSE67324.

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Acknowledgements

This work was supported by the Howard Hughes Medical Institute (S.H.O. and D.M.S.), Ellison Medical Foundation Aging grant (D.M.S.), NIH (R01 CA103866 and AI47389; D.M.S.), NIH (K08 CA198002; J.R.), Department of Defense PRCRP Career Development Award CA120198 (J.R.), NIH (R00 AG045144; Ö.H.Y.), NIH (R00 AG041765; D.W.L.), Center for the Study of Inflammatory Bowel Diseases from the Massachusetts General Hospital NIH (DK043351; Ö.H.Y.), NIH Cancer Center Support (core) grant P30-CA14051 (Ö.H.Y.), Kathy and Curt Marble Cancer Research Fund (Ö.H.Y.), American Federation of Aging Research (AFAR; Ö.H.Y.), and V Foundation Scholar grant (J.R. and Ö.H.Y.). M.D.M. is supported by a Koch MIT Ludwig Center post-doctoral fellowship, D.K. receives fellowship support from MGH (T32DK007191), and M.M.M. is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation. We thank the Koch Institute Swanson Biotechnology Center (SBC) for technical support, specifically the Hope Babette Tang (1983) Histology Facility and Kathleen Cormier. We thank S. Holder for superior histology and help with special stains. We thank P. Wisniewski and G. Paradis of the Whitehead flow cytometry and Koch core facilities, respectively, for their expertise in cell sorting. We thank members of the Yilmaz laboratory for discussions.

Author information

Author notes

    • Semir Beyaz
    • , Miyeko D. Mana
    •  & Jatin Roper

    These authors contributed equally to this work.

Affiliations

  1. The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA

    • Semir Beyaz
    • , Miyeko D. Mana
    • , Jatin Roper
    • , Dmitriy Kedrin
    • , Khristian E. Bauer-Rowe
    • , Michael E. Xifaras
    • , Adam Akkad
    • , Erika Arias
    • , Shweta Shinagare
    • , Monther Abu-Remaileh
    • , Maria M. Mihaylova
    • , Rizkullah Dogum
    • , David M. Sabatini
    •  & Ömer H. Yilmaz
  2. Division of Hematology/Oncology, Boston Children’s Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Semir Beyaz
    • , Guoji Guo
    •  & Stuart H. Orkin
  3. Division of Gastroenterology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA

    • Jatin Roper
  4. Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA

    • Dmitriy Kedrin
    • , Martin Selig
    • , G. Petur Nielsen
    • , Cristina R. Ferrone
    • , Vikram Deshpande
    •  & Ömer H. Yilmaz
  5. Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA

    • Assieh Saadatpour
    • , Luca Pinello
    •  & Guo-Cheng Yuan
  6. Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA

    • Sue-Jean Hong
    • , Monther Abu-Remaileh
    • , Maria M. Mihaylova
    • , George W. Bell
    •  & David M. Sabatini
  7. Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA

    • Yarden Katz
    • , David M. Sabatini
    •  & Ömer H. Yilmaz
  8. Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA

    • Dudley W. Lamming
  9. Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, Missisippi 39216, USA

    • Nitin Gupta

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Contributions

Ö.H.Y., S.B., M.D.M. and J.R. performed all experiments, and participated in their design and interpretation. J.R. optimized the colonoscopy transplantation assay, with help from A.A., M.D.M. and Ö.H.Y. S.-J.H. performed the mRNA-sequencing and analysis, with help from G.W.B., S.B., L.P. and Y.K. K.E.B.-R., A.A. and M.D.M. performed and interpreted the immunohistochemistry and in situ hybridization, under the guidance of Ö.H.Y. S.B. performed the single-cell analysis, with assistance from M.E.X., R.D., G.G., G.-C.Y. and A.S. M.S. and G.P.N. performed electron microscopy and helped with its interpretation. S.S., V.D. and Ö.H.Y. performed all pathology on the mice with help from J.R., and participated in the design and interpretation of experiments. M.E.X., E.A., R.D., M.A.-R., M.M.M. and D.W.L. supplied HFD-fed mice and provided experimental support. C.R.F. and N.G. provided assistance with the acquisition of human samples, while D.K. performed and interpreted the human cell culture experiments. S.H.O. and D.M.S. participated in the design and interpretation of experiments. Ö.H.Y. wrote the paper with support from S.B., M.D.M. and J.R.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to David M. Sabatini or Ömer H. Yilmaz.

Extended data

Supplementary information

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    Supplementary Information

    This file comprises: Supplementary Figure 1, which shows the original uncropped images of western blots presented in Figure 3 and in Extended Data Figures 3, 6 and 7; Supplementary Notes, which include texts for clarifying analyses and discussion; and Supplementary Tables 1 – 2, which show the lists of primers used in qRT-PCR and single cell analysis respectively.

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    Supplementary Data

    This file contains the raw gene expression data for the single cell gene expression analyses.

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https://doi.org/10.1038/nature17173

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