High-fat diet enhances stemness and tumorigenicity of intestinal progenitors
Authors: Rizkullah Dogum
Michael E Xifaras
Semir Beyaz
Khristian E Bauer-Rowe
Guoji Guo
Martin Selig
Monther Abu-Remaileh
George W Bell
Sue-Jean Hong
Luca Pinello
Maria M Mihaylova
Ömer H Yilmaz
Adam Akkad
Dudley W Lamming
Erika Arias
Shweta Shinagare
Nitin Gupta
Vikram Deshpande
Miyeko D Mana
Guo-Cheng Yuan
Yarden Katz
Assieh Saadatpour
G Petur Nielsen
Stuart H Orkin
Jatin Roper
David M Sabatini
Dmitriy Kedrin
Cristina R Ferrone
Journal: Nature (2016)
Discipline: Multidisciplinary
Keywords: pro-obesity diets; tissue stem cells; progenitor cells; high-fat diet; HFD
Affiliations: The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA., 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., Division of Gastroenterology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA., Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA., Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA., Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA., Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA., Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA., 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. 

Retracted: No

PubPeer comments:
 Wenge Li et al. in Cell Stem Cell have questioned the validity and the extent of this study by Beyaz et al. as proper controlled diets were not used in the design of the experiments. In the Li et al. article, the editors of Cell Stem Cell have noted the concerns and made a statement. ,