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

Nature
Authors
Keywords
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.

Year of Publication
2016
Journal
Nature
Volume
531
Issue
7592
Pages
53-8
Date Published
2016 Mar 03
ISSN
1476-4687
URL
DOI
10.1038/nature17173
PubMed ID
26935695
PubMed Central ID
PMC4846772
Links
Grant list
R01 AI047389 / AI / NIAID NIH HHS / United States
R01 CA103866 / CA / NCI NIH HHS / United States
DK043351 / DK / NIDDK NIH HHS / United States
T32 DK007191 / DK / NIDDK NIH HHS / United States
P30 DK043351 / DK / NIDDK NIH HHS / United States
R00 AG041765 / AG / NIA NIH HHS / United States
K99 AG045144 / AG / NIA NIH HHS / United States
T32DK007191 / DK / NIDDK NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
K08 CA198002 / CA / NCI NIH HHS / United States
R37 AI047389 / AI / NIAID NIH HHS / United States
Howard Hughes Medical Institute / United States
R00 AG045144 / AG / NIA NIH HHS / United States
R01 CA120198 / CA / NCI NIH HHS / United States
R01 CA129105 / CA / NCI NIH HHS / United States
K99 AG041765 / AG / NIA NIH HHS / United States
AI47389 / AI / NIAID NIH HHS / United States