# Understanding the role of vagal FFAR3 in regulating glucose homeostasis

> **NIH NIH F31** · LOYOLA UNIVERSITY CHICAGO · 2020 · $36,390

## Abstract

PROJECT SUMMARY/ABSRACT
The goal of this F31 application is to elucidate the roles and mechanisms of FFAR3 signaling in the vagus nerve in regulating
glucose homeostasis. Proper regulation of energy metabolism requires sensing of nutrient and hormonal cues to coordinate
an appropriate behavioral and physiological response. Vagus nerve sensing of dietary nutrients or nutrient-stimulated
hormones has been demonstrated to regulate food intake, glucose homeostasis, and gut motility. The gut microbiome
ferments soluble non-digestible fiber to release short-chain fatty acids (SCFA’s) which can serve as signaling molecules
through G-protein coupled receptors. The SCFA’s, including acetate, propionate, and butyrate can bind free fatty acid
receptor 2 (FFAR2) and 3 (FFAR3). Increasing dietary fiber intake or directly supplementing SCFA’s has been shown to
improve host glucose homeostasis, but the molecular mechanisms mediating these effects are unclear. Direct vagal sensing
of gut microbiome produced SCFA’s via FFAR3 could contribute to regulation of glucose metabolism. We found that
propionate was decreased in the plasma of western diet (WD)-fed mice compared to normal chow (NC)-fed controls. When
obese mice received oral gavages of fecal microbiome transplantations (FMT) from lean NC-fed donors, their plasma
propionate levels increased, and fasting blood glucose decreased. Directly supplementing propionate in the water of WD-
fed mice lowered fasting glucose and improved glucose tolerance. Propionate is the most potent known endogenous ligand
for FFAR3, and FFAR3 KO mice exhibit disrupted glucose tolerance, so we hypothesized that FFAR3 expressed on the
vagus nerve connects microbiome-produced propionate and central nervous system control of glucose homeostasis. Indeed,
we found Ffar3 to be actively translated in vagal sensory neurons. Treatment of vagal cultures with the FFAR3 ligand,
propionate, activated the neurons and increased neuronal translation of Glp1r. Vagal GLP1R function and expression is
dysregulated in rodent models of obesity, but the molecular mechanisms are not well understood. We hypothesize that
propionate signals through FFAR3 in the vagus nerve to increase Glp1r expression and improve glucose homeostasis. We
will test this hypothesis through the following aims. Aim 1 will assess if propionate activates vagal neurons and increases
Glp1r translation via FFAR3 in vagal organotypic cultures. We will accomplish this by utilizing the ribotag genetic mouse
model which allows for cell-specific assessment of genes in translation. We will assess translation of glucoregulatory genes
after propionate stimulation in vagal ganglia expressing FFAR3, and ganglia from FFAR3KO mice. Aim 2 will assess
whether vagal FFAR3 is required for propionate to improve glucose intolerance in vivo in WD-fed male and female mice.
To accomplish this, we will utilize a novel FFAR3 floxed mouse model and genetically ablate FFAR3 only from vagal
neurons. We will chal...

## Key facts

- **NIH application ID:** 10068055
- **Project number:** 1F31DK126441-01
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** Tyler Cook
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $36,390
- **Award type:** 1
- **Project period:** 2020-09-15 → 2023-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10068055

## Citation

> US National Institutes of Health, RePORTER application 10068055, Understanding the role of vagal FFAR3 in regulating glucose homeostasis (1F31DK126441-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10068055. Licensed CC0.

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