High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

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From: Nature(Vol. 531, Issue 7592)
Publisher: Nature Publishing Group
Document Type: Report
Length: 12,904 words
Lexile Measure: 1580L

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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[sup.+] intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR- 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--dependent manner. Notably, HFD- and agonist-activated PPAR- signalling endow organoid-initiating capacity to progenitors, and enforced PPAR- signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR- activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.

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Gale Document Number: GALE|A463709206