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

Nature | 2016

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.

Pubmed ID: 26935695 RIS Download

Associated grants

  • Agency: NIDDK NIH HHS, United States
    Id: DK043351
  • Agency: NIDDK NIH HHS, United States
    Id: T32 DK007191
  • Agency: NIDDK NIH HHS, United States
    Id: P30 DK043351
  • Agency: NIA NIH HHS, United States
    Id: R00 AG041765
  • Agency: NIA NIH HHS, United States
    Id: K99 AG045144
  • Agency: NIDDK NIH HHS, United States
    Id: T32DK007191
  • Agency: NCI NIH HHS, United States
    Id: P30 CA014051
  • Agency: NCI NIH HHS, United States
    Id: P30-CA14051
  • Agency: NCI NIH HHS, United States
    Id: K08 CA198002
  • Agency: NIAID NIH HHS, United States
    Id: R37 AI047389
  • Agency: NIA NIH HHS, United States
    Id: R00 AG045144
  • Agency: NCI NIH HHS, United States
    Id: R01 CA120198
  • Agency: NCI NIH HHS, United States
    Id: R01 CA129105
  • Agency: NIA NIH HHS, United States
    Id: K99 AG041765
  • Agency: NIAID NIH HHS, United States
    Id: AI47389
  • Agency: Howard Hughes Medical Institute, United States
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI047389
  • Agency: NCI NIH HHS, United States
    Id: R01 CA103866

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