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Calorie Restriction activates a gastric Notch-FOXO1 pathway to expand Ghrelin cells

View ORCID ProfileWendy M. McKimpson, Sophia Spiegel, Maria Mukhanova, Michael Kraakman, Wen Du, Takumi Kitamoto, Junjie Yu, Utpal Pajvani, Domenico Accili
doi: https://doi.org/10.1101/2023.03.06.531352
Wendy M. McKimpson
1Department of Medicine, Division of Endocrinology, Columbia University, New York, NY
2Naomi Berrie Diabetes Center, Columbia University, New York, NY
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  • ORCID record for Wendy M. McKimpson
  • For correspondence: wm2347@cumc.columbia.edu
Sophia Spiegel
1Department of Medicine, Division of Endocrinology, Columbia University, New York, NY
2Naomi Berrie Diabetes Center, Columbia University, New York, NY
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Maria Mukhanova
1Department of Medicine, Division of Endocrinology, Columbia University, New York, NY
2Naomi Berrie Diabetes Center, Columbia University, New York, NY
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Michael Kraakman
1Department of Medicine, Division of Endocrinology, Columbia University, New York, NY
2Naomi Berrie Diabetes Center, Columbia University, New York, NY
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Wen Du
1Department of Medicine, Division of Endocrinology, Columbia University, New York, NY
2Naomi Berrie Diabetes Center, Columbia University, New York, NY
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Takumi Kitamoto
1Department of Medicine, Division of Endocrinology, Columbia University, New York, NY
2Naomi Berrie Diabetes Center, Columbia University, New York, NY
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Junjie Yu
1Department of Medicine, Division of Endocrinology, Columbia University, New York, NY
2Naomi Berrie Diabetes Center, Columbia University, New York, NY
3Institute of Pharmaceutical Sciences, China Pharmaceutical University, Nanjing, Jiangsu, China
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Utpal Pajvani
1Department of Medicine, Division of Endocrinology, Columbia University, New York, NY
2Naomi Berrie Diabetes Center, Columbia University, New York, NY
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Domenico Accili
1Department of Medicine, Division of Endocrinology, Columbia University, New York, NY
2Naomi Berrie Diabetes Center, Columbia University, New York, NY
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Abstract

Calorie restriction increases lifespan. While some tissue-specific protective effects of calorie restriction have been described, the impact of calorie restriction on the gastrointestinal tract remains unclear. We found increased abundance of chromogranin A+, including orexigenic ghrelin+, endocrine cells in the stomach of calorie-restricted mice. This effect coincided with increased Notch target Hes1 and Notch ligand Jag1 and was reversed when Notch signaling was blocked using the γ-secretase inhibitor DAPT. Using primary cultures and genetically-modified reporter mice, we determined that increased endocrine cell abundance was due to altered stem and progenitor proliferation. Different from the intestine, calorie restriction decreased gastric Lgr5+ stem cells, while increasing a FOXO1/Neurog3+ subpopulation of endocrine progenitors in a Notch-dependent manner. Further, calorie restriction triggered nuclear localization of FOXO1, which was sufficient to promote endocrine cell differentiation. Taken together, the data indicate that calorie restriction promotes gastric endocrine cell differentiation triggered by active Notch signaling and regulated by FOXO1.

Competing Interest Statement

D.A. was a founder, director, stock holder, and chair of board of Forkhead Biotherapeutics Corp.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 07, 2023.
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Calorie Restriction activates a gastric Notch-FOXO1 pathway to expand Ghrelin cells
Wendy M. McKimpson, Sophia Spiegel, Maria Mukhanova, Michael Kraakman, Wen Du, Takumi Kitamoto, Junjie Yu, Utpal Pajvani, Domenico Accili
bioRxiv 2023.03.06.531352; doi: https://doi.org/10.1101/2023.03.06.531352
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Calorie Restriction activates a gastric Notch-FOXO1 pathway to expand Ghrelin cells
Wendy M. McKimpson, Sophia Spiegel, Maria Mukhanova, Michael Kraakman, Wen Du, Takumi Kitamoto, Junjie Yu, Utpal Pajvani, Domenico Accili
bioRxiv 2023.03.06.531352; doi: https://doi.org/10.1101/2023.03.06.531352

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