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High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

Author

Listed:
  • Semir Beyaz

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT
    Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School)

  • Miyeko D. Mana

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT)

  • Jatin Roper

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT
    Tufts Medical Center)

  • Dmitriy Kedrin

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT
    Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School)

  • Assieh Saadatpour

    (Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health)

  • Sue-Jean Hong

    (Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, MIT)

  • Khristian E. Bauer-Rowe

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT)

  • Michael E. Xifaras

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT)

  • Adam Akkad

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT)

  • Erika Arias

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT)

  • Luca Pinello

    (Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health)

  • Yarden Katz

    (Broad Institute of Harvard and MIT)

  • Shweta Shinagare

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT)

  • Monther Abu-Remaileh

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT
    Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, MIT)

  • Maria M. Mihaylova

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT
    Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, MIT)

  • Dudley W. Lamming

    (University of Wisconsin-Madison)

  • Rizkullah Dogum

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT)

  • Guoji Guo

    (Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School)

  • George W. Bell

    (Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, MIT)

  • Martin Selig

    (Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School)

  • G. Petur Nielsen

    (Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School)

  • Nitin Gupta

    (University of Mississippi Medical Center)

  • Cristina R. Ferrone

    (Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School)

  • Vikram Deshpande

    (Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School)

  • Guo-Cheng Yuan

    (Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health)

  • Stuart H. Orkin

    (Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School)

  • David M. Sabatini

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT
    Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, MIT
    Broad Institute of Harvard and MIT)

  • Ömer H. Yilmaz

    (The David H. Koch Institute for Integrative Cancer Research at MIT, MIT
    Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School
    Broad Institute of Harvard and MIT)

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.

Suggested Citation

  • Semir Beyaz & Miyeko D. Mana & Jatin Roper & Dmitriy Kedrin & Assieh Saadatpour & Sue-Jean Hong & Khristian E. Bauer-Rowe & Michael E. Xifaras & Adam Akkad & Erika Arias & Luca Pinello & Yarden Katz &, 2016. "High-fat diet enhances stemness and tumorigenicity of intestinal progenitors," Nature, Nature, vol. 531(7592), pages 53-58, March.
    • Handle: RePEc:nat:nature:v:531:y:2016:i:7592:d:10.1038_nature17173
    DOI: 10.1038/nature17173
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    Cited by:

    1. Alfredo Erazo-Oliveras & Mónica Muñoz-Vega & Mohamed Mlih & Venkataramana Thiriveedi & Michael L. Salinas & Jaileen M. Rivera-Rodríguez & Eunjoo Kim & Rachel C. Wright & Xiaoli Wang & Kerstin K. Landr, 2023. "Mutant APC reshapes Wnt signaling plasma membrane nanodomains by altering cholesterol levels via oncogenic β-catenin," Nature Communications, Nature, vol. 14(1), pages 1-28, December.
    2. Ozren Stojanović & Jordi Altirriba & Dorothée Rigo & Martina Spiljar & Emilien Evrard & Benedek Roska & Salvatore Fabbiano & Nicola Zamboni & Pierre Maechler & Françoise Rohner-Jeanrenaud & Mirko Traj, 2021. "Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
    3. Shuting Li & Chia-Wen Lu & Elia C. Diem & Wang Li & Melanie Guderian & Marc Lindenberg & Friederike Kruse & Manuela Buettner & Stefan Floess & Markus R. Winny & Robert Geffers & Hans-Hermann Richnow &, 2022. "Acetyl-CoA-Carboxylase 1-mediated de novo fatty acid synthesis sustains Lgr5+ intestinal stem cell function," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    4. Mergim Ramosaj & Sofia Madsen & Vanille Maillard & Valentina Scandella & Daniel Sudria-Lopez & Naoya Yuizumi & Ludovic Telley & Marlen Knobloch, 2021. "Lipid droplet availability affects neural stem/progenitor cell metabolism and proliferation," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    5. Carlos Sebastian & Christina Ferrer & Maria Serra & Jee-Eun Choi & Nadia Ducano & Alessia Mira & Manasvi S. Shah & Sylwia A. Stopka & Andrew J. Perciaccante & Claudio Isella & Daniel Moya-Rull & Maria, 2022. "A non-dividing cell population with high pyruvate dehydrogenase kinase activity regulates metabolic heterogeneity and tumorigenesis in the intestine," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    6. Yanying Wang & Jing Wang & Xiaoyu Li & Xushen Xiong & Jianyi Wang & Ziheng Zhou & Xiaoxiao Zhu & Yang Gu & Dan Dominissini & Lei He & Yong Tian & Chengqi Yi & Zusen Fan, 2021. "N1-methyladenosine methylation in tRNA drives liver tumourigenesis by regulating cholesterol metabolism," Nature Communications, Nature, vol. 12(1), pages 1-19, December.

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