PT  - JOURNAL ARTICLE
AU  - Wendy M. McKimpson
AU  - Sophia Spiegel
AU  - Maria Mukhanova
AU  - Michael Kraakman
AU  - Wen Du
AU  - Takumi Kitamoto
AU  - Junjie Yu
AU  - Utpal Pajvani
AU  - Domenico Accili
TI  - Calorie Restriction activates a gastric Notch-FOXO1 pathway to expand Ghrelin cells
AID  - 10.1101/2023.03.06.531352
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.03.06.531352
4099  - http://biorxiv.org/content/early/2023/03/07/2023.03.06.531352.short
4100  - http://biorxiv.org/content/early/2023/03/07/2023.03.06.531352.full
AB  - 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 StatementD.A. was a founder, director, stock holder, and chair of board of Forkhead Biotherapeutics Corp.