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

Nature (2016-03-05)
Semir Beyaz, Miyeko D Mana, Jatin Roper, Dmitriy Kedrin, Assieh Saadatpour, Sue-Jean Hong, Khristian E Bauer-Rowe, Michael E Xifaras, Adam Akkad, Erika Arias, Luca Pinello, Yarden Katz, Shweta Shinagare, Monther Abu-Remaileh, Maria M Mihaylova, Dudley W Lamming, Rizkullah Dogum, Guoji Guo, George W Bell, Martin Selig, G Petur Nielsen, Nitin Gupta, Cristina R Ferrone, Vikram Deshpande, Guo-Cheng Yuan, Stuart H Orkin, David M Sabatini, Ömer H Yilmaz
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Oleic acid, ≥99% (GC)
Sigma-Aldrich
Lipid Mixture 1, Chemically Defined, liquid, sterile-filtered, BioReagent, suitable for cell culture
Sigma-Aldrich
Toluidine Blue, for microscopy (Hist., Vit.)
Sigma-Aldrich
Anti-γ-Tubulin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution

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