In a new study, researchers have found how obesity — particularly, a high-fat diet — changes the function of intestinal stem and progenitor cells, and skew their activity toward tumor formation in mouse models.
The study, “High-fat diet enhances stemness and tumorigenicity of intestinal progenitors,” was published in the journal Nature.
Several studies have linked obesity to colon cancer incidence. However, it was still largely unknown how stem and progenitor cells in our intestines respond to obesity-inducing diets, and how these diets potentially change stem cells with the potential to initiate tumors.
A team of researchers at the David H. Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology (MIT) in Cambridge, Massachusetts, tackled this question and investigated how long-term, high-fat diet-induced obesity influences intestinal stem and progenitor cell functions, and how this can lead to disease.
Researchers maintained mice on a long-term high-fat diet (60 percent fat) for 9 to 14 months. They discovered that high-fat diet-induced obesity increased the numbers and function of Lgr5+ intestinal stem cells in the mice. Moreover, this effect was found to be not restricted to the stem cell population, but that high-fat diet-induced obesity also conferred features of stemness to non-stem-cell progenitors.
Researchers showed that this phenotype is mediated via high-fat diet activation of a robust peroxisome proliferator-activated receptor delta (PPAR-δ) signature in intestinal stem cells and non-intestinal stem cells (further shown using a pharmacological activator of PPAR-δ, and not a high-fat diet, which resulted in the same phenotype).
Using intestinal organoid cultures (small in vitro versions of intestine generated by adult intestinal crypts or adult intestinal stem cells), researchers showed that treating these cultures with fatty acid constituents of the high-fat diet resulted in enhanced self-renewal potential, hence stemness capacity of these organoid cultures. This was, once gain, shown to be dependent on PPAR-δ signaling, and resulted in the capacity of organoids cultures, after loss of the tumor suppressor gene Apc, to form in vivo tumors.
Overall, the results showed how diet modulates signaling pathways, in this case high-fat diet-modulated PPAR-δ activation, that changes the function of intestinal stem and progenitor cells, but most importantly their capacity to initiate tumors.