High-fat diet enhances stemness and tumorigenicity of intestinal progenitors
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; Ferrone, Cristina R.; Deshpande, Vikram; Yuan, Guo-Cheng; Orkin, Stuart H.; Beyaz, Semir; Mana, Miyeko; Roper, Jatin; Kedrin, Dmitriy; Bauer-Rowe, Khristian E.; Xifaras, Michael; Akkad, Adam; Arias, Erika; Shinagare, Shweta; Abu-Remaileh, Monther; Dogum, Rizkullah; Sabatini, David; Yilmaz, Omer; Mihaylova, Maria M.; ... Show more Show less
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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.
Date issued
2016-03Department
Massachusetts Institute of Technology. Department of Biology; Whitehead Institute for Biomedical Research; Koch Institute for Integrative Cancer Research at MITJournal
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
ISSN
0028-0836
1476-4687