High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

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, Shweta Shinagare, Monther Abu-Remaileh, Maria M. Mihaylova, Dudley W. Lamming, Rizkullah Dogum, Guoji Guo, George W. Bell, Martin Selig, G. Petur Nielsen, Nitin Gupta, Cristina R. Ferrone, Vikram Deshpande, Guo-Cheng Yuan, Stuart H. Orkin, David M. Sabatini () and Ömer H. Yilmaz ()
Additional contact information
Semir Beyaz: The David H. Koch Institute for Integrative Cancer Research at MIT, MIT
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
Dmitriy Kedrin: The David H. Koch Institute for Integrative Cancer Research at MIT, MIT
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
Maria M. Mihaylova: The David H. Koch Institute for Integrative Cancer Research at MIT, 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
Ömer H. Yilmaz: The David H. Koch Institute for Integrative Cancer Research at MIT, MIT

Nature, 2016, vol. 531, issue 7592, 53-58

Abstract: 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.

Date: 2016
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DOI: 10.1038/nature17173

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