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

Animal study using mice and primary cell cultures to investigate the effects of calorie restriction on gastric cell composition.

“This study finds that calorie restriction promotes gastric endocrine cell differentiation through active Notch signaling and that the transcription factor FOXO1 regulates this process.”

Male and female mice, including wild-type and genetically modified reporter strains (Lgr5-GFP, Neurog3-GFP, FOXO1-Venus, FoxKR), as well as primary stomach cultures.

“We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice.”

Small sample sizes per group, typically ranging from 3 to 10 mice per experimental cohort.

“Body weight after female wild-type mice were fed ad libitum (AL, n = 4 mice) or 30% food restricted (CR, n = 10 mice) for 4 wk.”

The primary calorie restriction period was 4 weeks, with additional 5-day drug treatment periods in some cohorts.

“we calorie-restricted female mice by 30% of their daily food intake (CR) for 4 wk and assessed the abundance of gastric cell populations after food restriction.”

Calorie restriction increased the abundance of ghrelin-positive and chromogranin A-positive endocrine cells in the stomach.

“We report increased numbers of chromogranin A-positive (+), including orexigenic ghrelin+ cells, in the stomach of calorie-restricted mice.”

The increase in endocrine cells was mediated by active Notch signaling, as blocking Notch with DAPT reversed the effect.

“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.”

The transcription factor FOXO1 was required for this process, with nuclear activation of FOXO1 sufficient to promote endocrine cell differentiation.

“Further, activation of FOXO1 was sufficient to promote endocrine cell differentiation independent of Notch.”

The study was conducted in mice and primary cultures, and the specific trigger for Notch activation remains undetermined.

“It remains to be determined what triggers Notch activation.”