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

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

Author information

1
The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA.
2
Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
3
Division of Gastroenterology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA.
4
Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.
5
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
6
Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA.
7
Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
8
Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA.
9
Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, Missisippi 39216, USA.

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.

PMID:
26935695
PMCID:
PMC4846772
DOI:
10.1038/nature17173
[Indexed for MEDLINE]
Free PMC Article

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