@article{26e394356e1944fb9e1a5a3f6ebe9843,
title = "High-fat diet enhances stemness and tumorigenicity of intestinal progenitors",
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.",
author = "Semir Beyaz and Mana, {Miyeko D.} and Jatin Roper and Dmitriy Kedrin and Assieh Saadatpour and Hong, {Sue Jean} and Bauer-Rowe, {Khristian E.} and Xifaras, {Michael E.} and Adam Akkad and Erika Arias and Luca Pinello and Yarden Katz and Shweta Shinagare and Monther Abu-Remaileh and Mihaylova, {Maria M.} and Lamming, {Dudley W.} and Rizkullah Dogum and Guoji Guo and Bell, {George W.} and Martin Selig and Nielsen, {G. Petur} and Nitin Gupta and Ferrone, {Cristina R.} and Vikram Deshpande and Yuan, {Guo Cheng} and Orkin, {Stuart H.} and Sabatini, {David M.} and Yilmaz, {{\"O}mer H.}",
note = "Funding Information: Acknowledgements This work was supported by the Howard Hughes Medical Institute (S.H.O. and D.M.S.), Ellison Medical Foundation Aging grant (D.M.S.), NIH (R01 CA103866 and AI47389; D.M.S.), NIH (K08 CA198002; J.R.), Department of Defense PRCRP Career Development Award CA120198 (J.R.), NIH (R00 AG045144; {\"O}.H.Y.), NIH (R00 AG041765; D.W.L.), Center for the Study of Inflammatory Bowel Diseases from the Massachusetts General Hospital NIH (DK043351; {\"O}.H.Y.), NIH Cancer Center Support (core) grant P30-CA14051 ({\"O}.H.Y.), Kathy and Curt Marble Cancer Research Fund ({\"O}.H.Y.), American Federation of Aging Research (AFAR; {\"O}.H.Y.), and V Foundation Scholar grant (J.R. and {\"O}.H.Y.). M.D.M. is supported by a Koch MIT Ludwig Center post-doctoral fellowship, D.K. receives fellowship support from MGH (T32DK007191), and M.M.M. is a Robert Black Fellow of the Damon Runyon Cancer Research Foundation. We thank the Koch Institute Swanson Biotechnology Center (SBC) for technical support, specifically the Hope Babette Tang (1983) Histology Facility and Kathleen Cormier. We thank S. Holder for superior histology and help with special stains. We thank P. Wisniewski and G. Paradis of the Whitehead flow cytometry and Koch core facilities, respectively, for their expertise in cell sorting. We thank members of the Yilmaz laboratory for discussions. Publisher Copyright: {\textcopyright} 2016 Macmillan Publishers Limited. All rights reserved.",
year = "2016",
month = mar,
day = "2",
doi = "10.1038/nature17173",
language = "English (US)",
volume = "531",
pages = "53--58",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7592",
}
