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. A high-fat diet increases the number of intestinal stem cells in mammals, both in vivo and in intestinal organoids; a pathway that involves PPAR-δ confers organoid-initiating capacity to non-stem cells and induces them to form in vivo tumours after loss of the Apc tumour suppressor. How obesity-inducing diets modulate tissue stem cell function and influence pathologies such as cancer is not clear. This study shows that a high-fat diet increases the number of intestinal stem cells in mammals in vivo and in intestinal organoids treated with fatty acids. The authors find that a pathway involving peroxisome proliferator-activated receptor delta (PPAR-δ) confers organoid-initiating capacity to non-stem cells, and demonstrate that the pathway induces non-stem cells to form tumors in vivo following the loss of the Apc tumour suppressor.