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 SeligG. Petur Nielsen, Nitin Gupta, Cristina R. Ferrone, Vikram Deshpande, Guo Cheng Yuan, Stuart H. Orkin, David M. Sabatini, Ömer H. Yilmaz

Research output: Contribution to journalArticlepeer-review

272 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)53-58
Number of pages6
JournalNature
Volume531
Issue number7592
DOIs
StatePublished - Mar 2 2016
Externally publishedYes

ASJC Scopus subject areas

  • General

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