Nature. 2016 Mar 3;531(7592):53-8.
High-fat diet enhances stemness and tumorigenicity of intestinal progenitors.
Beyaz S1,2, Mana MD1, Roper J1,3, Kedrin D1,4, Saadatpour A5, Hong SJ6, Bauer-Rowe KE1, Xifaras ME1, Akkad A1, Arias E1, Pinello L5, Katz Y7, Shinagare S1, Abu-Remaileh M1,6, Mihaylova MM1,6, Lamming DW8, Dogum R1, Guo G2, Bell GW6, Selig M4, Nielsen GP4, Gupta N9, Ferrone CR4, Deshpande V4, Yuan GC5, Orkin SH2, Sabatini DM1,6,7, Yilmaz ÖH1,4,7.
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.
TRIAL REGISTRATION: ClinicalTrials.gov .