# Gastric X/A Like Cells in Health and Diseases

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $312,000

## Abstract

Project Abstract
 New insights from our studies and others indicate that the gastric mucosa may sense overall energy
balance and control metabolic rate through fine-tuning the production of two counteracting hormones: ghrelin
and nesfatin-1, in X/A like cells. Ghrelin, a 28-amino acid gastric peptide hormone, was originally identified as
an orexigenic factor, and is the only known circulating hormone able to initiate food intake. X/A like cells has
been discovered to also secrete the anorexigenic hormone nesfatin-1. Our data indicate that the balance of
ghrelin and nesfatin-1 secretion regulates nutrient intake. Our studies also indicate that the mechanistic target
of rapamycin (mTOR) signaling pathway in the gastric mucosa plays a critical role in the coordination of
nutrient availability, ingestive behavior and metabolic activity. Based on these observations, we hypothesize
that mTOR signaling regulates fuel sensing via gastric X/A like endocrine cells. This signaling pathway
coordinates overall energy balance by differential regulation of the orexigenic hormone ghrelin and the
anorexigenic hormone nesfatin-1. We propose 3 specific aims to investigate the function of the gastric mTOR
pathway in the production of these peptides and thus their effects on appetite control and energy expenditure.
Aim 1 is designed to test the hypothesis that organismal fuel status affects phosphorylation of mTOR in gastric
X/A like cells, and that mTOR signaling differentially regulates ghrelin and nesfatin-1 production. Aim 2 will first
examine the alternative AMPK-HDAC5-mTOR signaling pathway in the regulation of ghrelin and nesfatin-1.
We will then test the hypothesis that S6K1 and 4EBP1 are mTOR downstream molecules regulating the
reciprocal translation of ghrelin and nesfatin-1. Aim 3 will demonstrate that gastric mTOR signaling affects food
intake, energy expenditure and body weight in mice vial acyl-ghrelin and nesfatin-1. Completion of this
proposal will advance our understanding of the interaction between gastric X/A like cells and nutrient intake.
These findings suggest a completely new therapeutic approach directed at gastric sites.

## Key facts

- **NIH application ID:** 9934188
- **Project number:** 5R01DK112755-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** MICHAEL W. MULHOLLAND
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $312,000
- **Award type:** 5
- **Project period:** 2018-09-13 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934188

## Citation

> US National Institutes of Health, RePORTER application 9934188, Gastric X/A Like Cells in Health and Diseases (5R01DK112755-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934188. Licensed CC0.

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