RT Journal Article
SR Electronic
T1 Calorie Restriction activates a gastric Notch-FOXO1 pathway to expand Ghrelin cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.03.06.531352
DO 10.1101/2023.03.06.531352
A1 Wendy M. McKimpson
A1 Sophia Spiegel
A1 Maria Mukhanova
A1 Michael Kraakman
A1 Wen Du
A1 Takumi Kitamoto
A1 Junjie Yu
A1 Utpal Pajvani
A1 Domenico Accili
YR 2023
UL http://biorxiv.org/content/early/2023/03/07/2023.03.06.531352.abstract
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.