A High-Fat Diet Promotes Intestinal Stemness and Tumorigenesis

Intestinal stem and progenitor cells respond to dietary changes, and are the putative colorectal cancer cells of origin. However, despite epidemiologic studies implicating obesity as a risk factor for colon cancer, the effects of pro-obesity diets on intestinal stem cell (ISC) function and the propensity to form tumors are not well understood. Beyaz, Mana, Roper, and colleagues used mice maintained on a long-term high-fat diet (HFD; 60% fat) to investigate the effects of obesity on ISCs. In addition to a higher body mass, HFD-fed mice had shorter small intestines and reduced villi length, but had an increased crypt depth and number of Lgr5⁺ ISCs, suggesting that the HFD increased the number and self-renewing activity of ISCs at the expense of differentiation. Further, after lethal irradiation, HFD mice had more proliferating crypts with more ISCs than control mice, suggesting that an HFD enhances the regenerative capacity of ISCs. Unlike control cells, HFD-derived ISCs were able to form 3-D organoids in the absence of Paneth cells that are part of the normal ISC niche. Additionally, components of the HFD such as palmitic acid or oleic acid were sufficient to induce stem-cell phenotypes in organoids. RNA sequencing of Lgr5⁺ ISCs from HFD-fed mice revealed increased expression of peroxisome proliferator-activated receptor δ (PPARδ) target proteins, and a PPARδ agonist phenocopied the effect of an HFD, increasing the number of Lgr5⁺ ISCs in vivo and promoting their self-renewing capacity in organoid cultures, indicating that PPARδ regulates fatty-acid driven stemness. Mice on an HFD had an increased rate of spontaneous adenoma and carcinoma tumorigenesis, and in Apc-null ISCs transplanted into recipient colons, treatment with a PPARδ agonist increased the formation of adenomas. Taken together, these results indicate that an HFD promotes the self-renewing capacity of ISCs and non–stem-cell progenitor cells via activation of PPARδ signaling and suggest a mechanistic link between obesity and tumor initiation.

Beyaz S, Mana MD, Roper J, Kedrin D, Saadatpour A, Hong S-J, et al. High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 2016;531:53–58.