High-fat diet enhances stemness and tumorigenicity of intestinal progenitors
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Sabatini_High fat diet.pdf
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5.94 MB
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Author(s)
Saadatpour, Assieh
Hong, Sue-Jean
Pinello, Luca
Katz, Yarden
Lamming, Dudley W.
Guo, Guoji
Bell, George W.
Selig, Martin
Nielsen, G. Petur
Gupta, Nitin
Date Issued
March 2016
Journal
Nature
Publisher
Nature Publishing Group
Citation
Beyaz, Semir et al. “High-Fat Diet Enhances Stemness and Tumorigenicity of Intestinal Progenitors.” Nature 531.7592 (2016): 53–58.
Version
Author's final manuscript
Abstract
Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we find that high fat diet (HFD)-induced obesity augments the numbers and function of Lgr5[superscript +] intestinal stem-cells (ISCs) of the mammalian intestine. Mechanistically, HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-d) signature in intestinal stem and (nonISC) progenitor cells, and pharmacologic activation of PPAR-d 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-d dependent manner. Interestingly, HFD- and agonist-activated PPAR-d signaling endow organoidinitiating capacity to progenitors, and enforced PPAR-d signaling permits these progenitors to form in vivo tumors upon loss of the tumor suppressor Apc. These findings highlight how dietmodulated PPAR-d activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumors.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Koch Institute for Integrative Cancer Research at MIT
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Creative Commons Attribution-Noncommercial-Share Alike
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DOI of Published Version
https://doi.org/10.1038/nature17173
