High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

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...

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Bibliographic Details
Main Authors: 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.
Other Authors: Massachusetts Institute of Technology. Department of Biology
Format: Article
Language:en_US
Published: Nature Publishing Group 2017
Online Access:http://hdl.handle.net/1721.1/106594
https://orcid.org/0000-0002-5516-4008
https://orcid.org/0000-0001-6093-7282
https://orcid.org/0000-0002-1446-7256
https://orcid.org/0000-0002-7577-4612
Description
Summary: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.

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