# The Role of Glutamate in the Control of Food Intake

> **NIH NIH R01** · WASHINGTON STATE UNIVERSITY · 2020 · $474,982

## Abstract

ABSTRACT
This application for renewal continues an enduring interest in neural mechanisms by which gastrointestinal
(GI) satiation signals are communicated to the hindbrain nucleus of the solitary tract (NTS) by vagal
afferents and are integrated with other controls of food intake. Glutamate is the principal neurotransmitter
released by vagal afferent terminals in the nucleus tractus solitarius (NTS). As such, glutamate receptors in
the NTS are pivotal to the transmission and processing of satiation signals. Our published results,
demonstrating that hindbrain injections of N-methyl-D-aspartate-type glutamate receptor (NMDAR)
antagonists increase meal size and prevent reduction of food intake by cholecystokinin (CCK) support this
assertion. Although vagal afferent activation by GI stimuli reduce meal size, central neuropeptides and
circulating hormones also control food intake by controlling meal size, suggesting that they may modulate or
imitate the effects of GI stimuli. We postulate that brain peptides interact with NMDAR to control meal size
by modulating the strength of glutamatergic vagal afferent synapses in the NTS. Our preliminary results
suggest that interaction of vagal afferent NMDAR and melanocortin 4 receptors (MC4R) triggers long-lasting
changes in vagal afferent synapsin phosphorylation that are consistent with strengthened vagal afferent
synaptic function. Experiments of Aim 1 utilize pharmacological, immunochemical, chemogenetic and
electrophysiological approaches to determine the nature of NMDAR participation in MC4R effects on vagal
afferent synaptic function and control of meal size. Vagal afferents express type 1 and type 2 NPY
receptors (Y1R and Y2R) as well as MC4R and NMDAR. We find that NTS injection of NPY or the Y2R
agonist, PYY 3-36, increases food intake, an effect that is attenuated by NTS co-injection of SP-cAMP. In
Aim 2 of the application we test the hypothesis that vagal afferent Y2R control food intake by antagonizing
MC4R effects on PKA activation, synapsin phosphorylation and vagal afferent synaptic strength. Our long-
term goal is to determine how NMDAR participate in modulation of vagal afferent synaptic strength to reduce
food intake. A detailed appreciation of the mechanisms by which peptides and hormone interact with
NMDAR to control of food intake is of significance to human health because it may provide avenues for
therapeutic intervention in eating disorders and obesity.

## Key facts

- **NIH application ID:** 9926840
- **Project number:** 5R01DK052849-20
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Suzanne M Appleyard
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $474,982
- **Award type:** 5
- **Project period:** 1998-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9926840

## Citation

> US National Institutes of Health, RePORTER application 9926840, The Role of Glutamate in the Control of Food Intake (5R01DK052849-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9926840. Licensed CC0.

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