Study summary · research use only
Calorie restriction activates a gastric Notch-FOXO1 pathway to expand ghrelin cells
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This mouse study examined how calorie restriction affects gastric ghrelin cells via a Notch-FOXO1 pathway. Calorie-restricted mice showed increased numbers of chromogranin A-positive cells, including orexigenic ghrelin+ cells, along with increased Notch target Hes1 and Notch ligand Jag1; this effect was reversed by the gamma-secretase inhibitor DAPT. Using primary cultures and reporter mice, the authors report that increased endocrine cell abundance reflected altered Lgr5+ stem and Neurog3+ endocrine progenitor cell proliferation, and that, unlike in the intestine, calorie restriction decreased gastric Lgr5+ stem cells while increasing a FOXO1/Neurog3+ endocrine progenitor subpopulation in a Notch-dependent manner. The Notch inhibitor PF-03084014 or the ghrelin receptor antagonist GHRP-6 reversed these effects, and tirzepatide additionally expanded ghrelin+ cells in mice.
Abstract
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.
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