This article has been updated


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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


Primary accessions

Gene Expression Omnibus

Data deposits

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


  1. 1.

    et al. mTORC1 in the Paneth cell niche couples intestinal stem-cell function to calorie intake. Nature 486, 490–495 (2012)

  2. 2.

    et al. Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449, 1003–1007 (2007)

  3. 3.

    , & Dietary and metabolic control of stem cell function in physiology and cancer. Cell Stem Cell 14, 292–305 (2014)

  4. 4.

    et al. Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts. Nature 469, 415–418 (2011)

  5. 5.

    et al. National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 377, 557–567 (2011)

  6. 6.

    & Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nature Rev. Cancer 4, 579–591 (2004)

  7. 7.

    , , , & The interaction of a high-fat diet and regular moderate intensity exercise on intestinal polyp development in ApcMin/+ mice. Cancer Prev. Res. (Phila.) 2, 641–649 (2009)

  8. 8.

    et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457, 608–611 (2009)

  9. 9.

    et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152, 25–38 (2013)

  10. 10.

    et al. Reprogramming of the circadian clock by nutritional challenge. Cell 155, 1464–1478 (2013)

  11. 11.

    & The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 53 (suppl. 3), S215–S219 (2004)

  12. 12.

    , , & Robust Cre-mediated recombination in small intestinal stem cells utilizing the Olfm4 locus. Stem Cell Reports 3, 234–241 (2014)

  13. 13.

    et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459, 262–265 (2009)

  14. 14.

    et al. Ascl2 acts as an R-spondin/Wnt-responsive switch to control stemness in intestinal crypts. Cell Stem Cell 16, 158–170 (2015)

  15. 15.

    et al. Epithelial Pten is dispensable for intestinal homeostasis but suppresses adenoma development and progression after Apc mutation. Nature Genet. 40, 1436–1444 (2008)

  16. 16.

    et al. Defining high-fat-diet rat models: metabolic and molecular effects of different fat types. J. Mol. Endocrinol. 36, 485–501 (2006)

  17. 17.

    , & The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nature Rev. Cancer 12, 181–195 (2012)

  18. 18.

    & Fat and beyond: the diverse biology of PPARγ. Annu. Rev. Biochem. 77, 289–312 (2008)

  19. 19.

    & Physiological functions of peroxisome proliferator-activated receptor β. Physiol. Rev. 94, 795–858 (2014)

  20. 20.

    et al. A PML-PPAR-δ pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance. Nature Med. 18, 1350–1358 (2012)

  21. 21.

    et al. AMPK and PPARδ agonists are exercise mimetics. Cell 134, 405–415 (2008)

  22. 22.

    & Stem cells, self-renewal, and differentiation in the intestinal epithelium. Annu. Rev. Physiol. 71, 241–260 (2009)

  23. 23.

    et al. Transcription factor achaete scute-like 2 controls intestinal stem cell fate. Cell 136, 903–912 (2009)

  24. 24.

    et al. The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers. EMBO J. 31, 3079–3091 (2012)

  25. 25.

    & Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347, 78–81 (2015)

  26. 26.

    et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature 441, 475–482 (2006)

  27. 27.

    & Tumour heterogeneity and cancer cell plasticity. Nature 501, 328–337 (2013)

  28. 28.

    et al. PPARβ/δ governs Wnt signaling and bone turnover. Nature Med. 19, 608–613 (2013)

  29. 29.

    et al. Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer. Proc. Natl Acad. Sci. USA 106, 6315–6320 (2009)

  30. 30.

    et al. Preferential induction of EphB4 over EphB2 and its implication in colorectal cancer progression. Cancer Res. 69, 3736–3745 (2009)

  31. 31.

    et al. Oncogenic β-catenin is required for bone morphogenetic protein 4 expression in human cancer cells. Cancer Res. 62, 2744–2748 (2002)

  32. 32.

    , , & Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–47 (2016)

  33. 33.

    , , , & Impact of diet-induced obesity on intestinal stem cells: hyperproliferation but impaired intrinsic function that requires insulin/IGF1. Endocrinology 155, 3302–3314 (2014)

  34. 34.

    et al. High fat diet causes depletion of intestinal eosinophils associated with intestinal permeability. PLoS ONE 10, e0122195 (2015)

  35. 35.

    et al. Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth. Proc. Natl Acad. Sci. USA 111, 7084–7089 (2014)

  36. 36.

    et al. Crosstalk between peroxisome proliferator-activated receptor δ and VEGF stimulates cancer progression. Proc. Natl Acad. Sci. USA 103, 19069–19074 (2006)

  37. 37.

    , & Genetic disruption of PPARδ decreases the tumorigenicity of human colon cancer cells. Proc. Natl Acad. Sci. USA 98, 2598–2603 (2001)

  38. 38.

    et al. Targeted genetic disruption of peroxisome proliferator-activated receptor-delta and colonic tumorigenesis. J. Natl. Cancer Inst. 101, 762–767 (2009)

  39. 39.

    et al. Activation of nuclear hormone receptor peroxisome proliferator-activated receptor-δ accelerates intestinal adenoma growth. Nature Med. 10, 245–247 (2004)

  40. 40.

    et al. Effects of peroxisome proliferator-activated receptor δ on placentation, adiposity, and colorectal cancer. Proc. Natl Acad. Sci. USA 99, 303–308 (2002)

  41. 41.

    et al. Colorectal cancers in a new mouse model of familial adenomatous polyposis: influence of genetic and environmental modifiers. Lab. Invest. 84, 1619–1630 (2004)

  42. 42.

    & In situ hybridization to identify gut stem cells. Curr. Protoc. Stem Cell Biol. Chapter 2, Unit 2F.1 (2010)

  43. 43.

    & In vitro expansion and genetic modification of gastrointestinal stem cells in spheroid culture. Nature Protocols 8, 2471–2482 (2013)

  44. 44.

    , & TopHat: discovering splice junctions with RNA-Seq. Bioinformatics 25, 1105–1111 (2009)

  45. 45.

    & Differential expression analysis for sequence count data. Genome Biol. 11, R106 (2010)

  46. 46.

    , , & Analysis of chromatin-state plasticity identifies cell-type-specific regulators of H3K27me3 patterns. Proc. Natl Acad. Sci. USA 111, E344–E353 (2014)

  47. 47.

    & Visualizing Data using t-SNE. J. Mach. Learn. Res. 9, 2579–2605 (2008)

  48. 48.

    & Controlling the false discovery rate – a practical and powerful approach to multiple testing. J. Roy. Stat. Soc. B 57, 289–300 (1995)

Download references


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.


  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


  1. Search for Semir Beyaz in:

  2. Search for Miyeko D. Mana in:

  3. Search for Jatin Roper in:

  4. Search for Dmitriy Kedrin in:

  5. Search for Assieh Saadatpour in:

  6. Search for Sue-Jean Hong in:

  7. Search for Khristian E. Bauer-Rowe in:

  8. Search for Michael E. Xifaras in:

  9. Search for Adam Akkad in:

  10. Search for Erika Arias in:

  11. Search for Luca Pinello in:

  12. Search for Yarden Katz in:

  13. Search for Shweta Shinagare in:

  14. Search for Monther Abu-Remaileh in:

  15. Search for Maria M. Mihaylova in:

  16. Search for Dudley W. Lamming in:

  17. Search for Rizkullah Dogum in:

  18. Search for Guoji Guo in:

  19. Search for George W. Bell in:

  20. Search for Martin Selig in:

  21. Search for G. Petur Nielsen in:

  22. Search for Nitin Gupta in:

  23. Search for Cristina R. Ferrone in:

  24. Search for Vikram Deshpande in:

  25. Search for Guo-Cheng Yuan in:

  26. Search for Stuart H. Orkin in:

  27. Search for David M. Sabatini in:

  28. Search for Ömer H. Yilmaz in:


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

PDF files

  1. 1.

    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.

Excel files

  1. 1.

    Supplementary Data

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

About this article

Publication history





Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.