High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Beyaz, S; Mana, MD; Roper, J; Kedrin, D; Saadatpour, A; Hong, S-J; Bauer-Rowe, KE; Xifaras, ME; Akkad, A; Arias, E; Pinello, L; Katz, Y; Shinagare, S; Abu-Remaileh, M; Mihaylova, MM; Lamming, DW; Dogum, R; Guo, G; Bell, GW; Selig, M; Nielsen, GP; Gupta, N; Ferrone, CR; Deshpande, V; Yuan, G-C; Orkin, SH; Sabatini, DM; Yilmaz, ÖH

Published Date

  • March 3, 2016

Published In

Volume / Issue

  • 531 / 7592

Start / End Page

  • 53 - 58

PubMed ID

  • 26935695

Pubmed Central ID

  • PMC4846772

Electronic International Standard Serial Number (EISSN)

  • 1476-4687

Digital Object Identifier (DOI)

  • 10.1038/nature17173


  • eng

Conference Location

  • England