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-?) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-? 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-?-dependent manner. Notably, HFD- and agonist-activated PPAR-? signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-? signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-? activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.

SUBMITTER: Beyaz S 

PROVIDER: S-EPMC4846772 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature