High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.
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.
Beyaz, S; Mana, MD; Roper, J; Kedrin, D; Saadatpour, A; Hong, S-J; Bauer-Rowe, KE; Xifaras, ME; Akkad, A; Arias, E; Pinello, L; Katz, Y; Shinagare, S; Abu-Remaileh, M; Mihaylova, MM; Lamming, DW; Dogum, R; Guo, G; Bell, GW; Selig, M; Nielsen, GP; Gupta, N; Ferrone, CR; Deshpande, V; Yuan, G-C; Orkin, SH; Sabatini, DM; Yilmaz, ÖH
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