Beyaz, S., Mana, M. D., Roper, J., Kedrin, D., Saadatpour, A., Hong, S. J., Bauer-Rowe, K. E., Xifaras, M. E., Akkad, A., Arias, E., Pinello, L., Katz, Y., Shinagare, S., Abu-Remaileh, M., Mihaylova, M. M., Lamming, D. W., Dogum, R., Guo, G., Bell, G. W., Selig, M., Nielsen, G. P., Gupta, N., Ferrone, C. R., Deshpande, V., Yuan, G. C., Orkin, S. H., Sabatini, D. M., Yilmaz, O. H. (March 2016) High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature, 531 (7592). pp. 53-8. ISSN 1476-4687 (Electronic)0028-0836 (Linking)
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-delta) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-delta 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-delta-dependent manner. Notably, HFD- and agonist-activated PPAR-delta signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-delta signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Animals Cell Count Cell Self Renewal/drug effects Cell Transformation, Neoplastic/*drug effects Colonic Neoplasms/*pathology Diet, High-Fat/*adverse effects Female Genes, APC Humans Intestines/*pathology Male Mice Obesity/chemically induced/pathology Organoids/drug effects/metabolism/pathology PPAR delta/metabolism Signal Transduction/drug effects Stem Cell Niche/drug effects Stem Cells/*drug effects/metabolism/*pathology beta Catenin/metabolism |
| Subjects: | Investigative techniques and equipment > cell culture > cancer organoids diseases & disorders > cancer > cancer types > colon cancer diseases & disorders > cancer > cancer types > colon cancer organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells organs, tissues, organelles, cell types and functions > cell types and functions > cell types > stem cells |
| CSHL Authors: | |
| Communities: | CSHL labs > Beyaz lab |
| Depositing User: | Matt Covey |
| Date: | 3 March 2016 |
| Date Deposited: | 02 Feb 2018 20:03 |
| Last Modified: | 02 Feb 2018 20:03 |
| PMCID: | PMC4846772 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/36047 |
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