Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells.

Autor:	McKimpson WM; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA., Spiegel S; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA., Mukhanova M; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA., Kraakman M; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA., Du W; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA., Kitamoto T; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA., Yu J; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA., Deng Z; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA., Pajvani U; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA., Accili D; Department of Medicine, Division of Endocrinology, Columbia University, New York, NY, USA.; Naomi Berrie Diabetes Center, Columbia University, New York, NY, USA.
Jazyk:	angličtina
Zdroj:	The Journal of cell biology [J Cell Biol] 2024 Oct 07; Vol. 223 (10). Date of Electronic Publication: 2024 Jul 03.
DOI:	10.1083/jcb.202305093
Abstrakt:	Calorie restriction increases lifespan. Among the tissue-specific protective effects of calorie restriction, the impact on the gastrointestinal tract remains unclear. We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice. This effect was accompanied by increased Notch target Hes1 and Notch ligand Jag1 and was reversed by blocking Notch with DAPT, a gamma-secretase inhibitor. Primary cultures and genetically modified reporter mice show that increased endocrine cell abundance is due to altered Lgr5+ stem and Neurog3+ endocrine progenitor cell 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, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch. The Notch inhibitor PF-03084014 or ghrelin receptor antagonist GHRP-6 reversed the phenotypic effects of calorie restriction in mice. Tirzepatide additionally expanded ghrelin+ cells in mice. In summary, calorie restriction promotes Notch-dependent, FOXO1-regulated gastric endocrine cell differentiation. (© 2024 McKimpson et al.)
Databáze:	MEDLINE
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