High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

Semir Beyaz; Miyeko D. Mana; Jatin Roper; Dmitriy Kedrin; Assieh Saadatpour; Sue Jean Hong; Khristian E. Bauer-Rowe; Michael E. Xifaras; Adam Akkad; Erika Arias; Luca Pinello; Yarden Katz; Shweta Shinagare; Monther Abu-Remaileh; Maria M. Mihaylova; Dudley W. Lamming; Rizkullah Dogum; Guoji Guo; George W. Bell; Martin Selig; G. Petur Nielsen; Nitin Gupta; Cristina R. Ferrone; Vikram Deshpande; Guo Cheng Yuan; Stuart H. Orkin; David M. Sabatini; Ömer H. Yilmaz

doi:10.1038/nature17173

High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

Semir Beyaz, Miyeko D. Mana, Jatin Roper, Dmitriy Kedrin, Assieh Saadatpour, Sue Jean Hong, Khristian E. Bauer-Rowe, Michael E. Xifaras, Adam Akkad, Erika Arias, Luca Pinello, Yarden Katz, Shweta Shinagare, Monther Abu-Remaileh, Maria M. Mihaylova, Dudley W. Lamming, Rizkullah Dogum, Guoji Guo, George W. Bell, Martin SeligG. Petur Nielsen, Nitin Gupta, Cristina R. Ferrone, Vikram Deshpande, Guo Cheng Yuan, Stuart H. Orkin, David M. Sabatini, Ömer H. Yilmaz

Research output: Contribution to journal › Article › peer-review

533 Scopus citations

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-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.

Original language	English (US)
Pages (from-to)	53-58
Number of pages	6
Journal	Nature
Volume	531
Issue number	7592
DOIs	https://doi.org/10.1038/nature17173
State	Published - Mar 2 2016
Externally published	Yes

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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., ... Yilmaz, Ö. H. (2016). High-fat diet enhances stemness and tumorigenicity of intestinal progenitors. Nature, 531(7592), 53-58. https://doi.org/10.1038/nature17173

Beyaz, S, Mana, MD, Roper, J, Kedrin, D, Saadatpour, A, Hong, SJ, Bauer-Rowe, KE, Xifaras, ME, Akkad, A, Arias, E, Pinello, L, Katz, Y, Shinagare, S, Abu-Remaileh, M, Mihaylova, MM, Lamming, DW, Dogum, R, Guo, G, Bell, GW, Selig, M, Nielsen, GP, Gupta, N, Ferrone, CR, Deshpande, V, Yuan, GC, Orkin, SH, Sabatini, DM & Yilmaz, ÖH 2016, 'High-fat diet enhances stemness and tumorigenicity of intestinal progenitors', Nature, vol. 531, no. 7592, pp. 53-58. https://doi.org/10.1038/nature17173

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title = "High-fat diet enhances stemness and tumorigenicity of intestinal progenitors",

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-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.",

author = "Semir Beyaz and Mana, {Miyeko D.} and Jatin Roper and Dmitriy Kedrin and Assieh Saadatpour and Hong, {Sue Jean} and Bauer-Rowe, {Khristian E.} and Xifaras, {Michael E.} and Adam Akkad and Erika Arias and Luca Pinello and Yarden Katz and Shweta Shinagare and Monther Abu-Remaileh and Mihaylova, {Maria M.} and Lamming, {Dudley W.} and Rizkullah Dogum and Guoji Guo and Bell, {George W.} and Martin Selig and Nielsen, {G. Petur} and Nitin Gupta and Ferrone, {Cristina R.} and Vikram Deshpande and Yuan, {Guo Cheng} and Orkin, {Stuart H.} and Sabatini, {David M.} and Yilmaz, {{\"O}mer H.}",

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AU - Beyaz, Semir

AU - Mana, Miyeko D.

AU - Roper, Jatin

AU - Kedrin, Dmitriy

AU - Saadatpour, Assieh

AU - Hong, Sue Jean

AU - Bauer-Rowe, Khristian E.

AU - Xifaras, Michael E.

AU - Akkad, Adam

AU - Arias, Erika

AU - Pinello, Luca

AU - Katz, Yarden

AU - Shinagare, Shweta

AU - Abu-Remaileh, Monther

AU - Mihaylova, Maria M.

AU - Lamming, Dudley W.

AU - Dogum, Rizkullah

AU - Guo, Guoji

AU - Bell, George W.

AU - Selig, Martin

AU - Nielsen, G. Petur

AU - Gupta, Nitin

AU - Ferrone, Cristina R.

AU - Deshpande, Vikram

AU - Yuan, Guo Cheng

AU - Orkin, Stuart H.

AU - Sabatini, David M.

AU - Yilmaz, Ömer H.

PY - 2016/3/2

Y1 - 2016/3/2

N2 - 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.

AB - 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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High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

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