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High-fat diet enhances stemness and tumorigenicity of intestinal progenitors
Open accessAbstract
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.
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Self-citation
Metadata
- Authors
- 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, Ö. H.
- Venue
- Nature
- Published
- 2016-03-02
- Volume
- 531
- Issue
- 7592
- Pages
- 53-58
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2290001148
- Cited by
- 845
- References
- 11
- FWCI
- 33.41
- Type
- journal article
- Language
- en
- Open access
- green
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