High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

Nature. 2016 Mar 3;531(7592):53-8. doi: 10.1038/nature17173.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Comment

MeSH terms

  • Animals
  • Cell Count
  • Cell Self Renewal / drug effects
  • Cell Transformation, Neoplastic / drug effects*
  • Colonic Neoplasms / pathology*
  • Diet, High-Fat / adverse effects*
  • Female
  • Genes, APC
  • Humans
  • Intestines / pathology*
  • Male
  • Mice
  • Obesity / chemically induced
  • Obesity / pathology
  • Organoids / drug effects
  • Organoids / metabolism
  • Organoids / pathology
  • PPAR delta / metabolism
  • Signal Transduction / drug effects
  • Stem Cell Niche / drug effects
  • Stem Cells / drug effects*
  • Stem Cells / metabolism
  • Stem Cells / pathology*
  • beta Catenin / metabolism


  • PPAR delta
  • beta Catenin

Associated data

  • GEO/GSE67324