Editors' ChoiceStem Cells

Fatty diet alters stem cells

Sci. Signal.  08 Mar 2016:
Vol. 9, Issue 418, pp. ec50
DOI: 10.1126/scisignal.aaf6180

Obesity and high-fat diet (HFD) are linked to increased risk for developing colon cancer. Precancerous adenomatous lesions in the intestine can arise from intestinal stem cells (ISCs) and their pluripotent daughters, progenitor cells. Beyaz et al. found that, compared with mice fed a standard diet, mice fed a HFD had more ISCs and fewer Paneth cells, which constitute the ISC niche and control ISC proliferation. In vivo assays and experiments with intestinal crypt explants demonstrated that ISCs from HFD mice had an increased ability to support regeneration and the formation of intestinal organoids in culture, even when they were separated from Paneth cells. Mice genetically predisposed to become obese on standard chow did not exhibit these ISC phenotypes, suggesting that the composition of the HFD, not the resulting obesity, was responsible for the effects on ISCs. The addition of fatty acids that are present in the HFD to the culture medium enhanced the organoid-forming ability of ISCs isolated from control mice. ISCs from HFD mice had increased expression of transcriptional targets of the peroxisome proliferator–activated receptor (PPAR) family of nuclear receptors, the most abundant of which in ISCs is PPAR-δ. Treating mice with a PPAR-δ agonist recapitulated many of the ISC phenotypes induced by HFD, and PPAR-δ was required for fatty acids to stimulate ISC activity in organoids derived from control mice. Several lines of evidence suggested that ISCs from mice fed a HFD or treated with the PPAR-δ agonist had increased Wnt signaling, which promotes ISC proliferation. HFD mice had an increased incidence of spontaneous intestinal tumors compared to controls. Progenitor cells from PPAR-δ agonist–treated mice exhibited increased tumor-forming ability in organoid cultures and promoted the formation of adenomas when implanted into wild-type mice fed a standard diet. Thus, fatty acids present in a HFD can fundamentally change the activity of intestinal stem and progenitor cells, thereby increasing the likelihood of these cells to form tumors. Luo and Puigserver discuss how these findings may relate to gastrointestinal and metabolic diseases.

S. Beyaz, M. D. Mana, J. Roper, D. Kedrin, A. Saadatpour, S.-J. Hong,
K. E. Bauer-Rowe, M. E. Xifaras, A. Akkad, E. Arias, L. Pinello, Y. Katz, S. Shinagare, M. Abu-Remaileh, M. M. Mihaylova, D. W. Lamming, R. Dogum, G. Guo, G. W. Bell, M. Selig, G. P. Nielsen, N. Gupta, C. R. Ferrone, V. Deshpande, G.-C. Yuan, S. H. Orkin, D. M. Sabatini, Ö. H. Yilmaz, High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature 531, 53–58 (2016). [PubMed]

C. Luo, P. Puigserver, Dietary fat promotes intestinal dysregulation. Nature 531, 42–43 (2016). [PubMed]