# Consequence and mechanism of diet-driven vagal remodeling on gut-brain feeding behavior

> **NIH NIH R01** · UNIVERSITY OF GEORGIA · 2021 · $447,205

## Abstract

PROJECT SUMMARY
Obesity is one of the defining public health problems of our time. At its root, increases in fat storage is caused
by an imbalance in energy homeostasis, favoring energy intake over expenditure. Physiological mechanisms are
in place to prevent excess caloric intake, yet these defense mechanisms fail in the face a modern food
environment that promotes food intake. This is underscored by the lack of efficacy of non-invasive strategies,
such as caloric restriction or medications, to sustain long-term weight loss. Thus, there is a critical need to
understand the pathophysiology leading to food overconsumption and develop novel strategies to promote
weight loss. The vagus nerve provides direct communication about nutrient intake from the gut to the brain.
Removing of the vagus in lean animals results in significant overeating when presented with palatable calorie
dense diets, suggesting a protective role of the vagus nerve to prevent overconsumption of calories. In obesity,
vagal communication of gut metabolic cues to the brain is impaired, and preventing vagal signaling results in
weight loss in animals fed high fat diet. The mechanisms for the switch from protection against, towards
promoting obesity are unclear, but we have recently demonstrated that chronic consumption of high fat diet
results in anatomical restructuring of vagal fibers in the brain. Therefore, we propose a new hypothesis that vagal
gut-brain axis is reprogramed in response to high fat diets to drive obesity. We use a combination of molecular
and genetic approaches to deconstruct the sensory vagus into cellular components based on their site of
innervation to fully elucidate the role of high fat feeding on vagal remodeling. In aim 1 we assess the impact of
diet on vagal fiber anatomy, synaptic function, and the behavioral consequences, including meal termination and
motivation for food. In aims 2 and 3 we consider the mechanisms by which diet causes vagal remodeling. We
hypothesize that a gut microbiota-driven immune response triggers the rewiring of the gut-brain axis. This is
supported by our previous work and preliminary data showing abnormal microbiota composition is necessary
and sufficient to alter vagal innervation in the NTS. In aim 2, we will use germ free rats and microbiota transplant
to determine 1) if microbiota dysbiosis is sufficient for vagal remodeling, and 2) if restoring a symbiotic microbiota
in obesity can normalize vagal signaling, feeding behavior and body weight. In aim 3 we will combine genetic
and molecular tools to investigate the recruitment of immune cells with the vagal afferent pathway as mediators
of diet-driven vagal maladaptation. Completion of these studies will identify vagal rewiring as a novel pathway in
the etiology of obesity, and establish microbiota and microglia as potential tools for the development of weight
loss strategies.
.

## Key facts

- **NIH application ID:** 10197124
- **Project number:** 5R01DK125890-02
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Claire de La Serre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $447,205
- **Award type:** 5
- **Project period:** 2020-07-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10197124

## Citation

> US National Institutes of Health, RePORTER application 10197124, Consequence and mechanism of diet-driven vagal remodeling on gut-brain feeding behavior (5R01DK125890-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10197124. Licensed CC0.

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