High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.
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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
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Journal | Nature
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Volume | 531
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Issue | 7592
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Pages | 53-8
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Date Published | 2016 Mar 03
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ISSN | 1476-4687
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URL | |
DOI | 10.1038/nature17173
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PubMed ID | 26935695
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PubMed Central ID | PMC4846772
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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
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