# Pathophysiological mechanisms in the brain's endogenous glucagon-like peptide 1 system mediated by obesogenic diets

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $655,971

## Abstract

Title: Pathophysiological mechanisms in the brain’s endogenous glucagon-like peptide 1 system mediated by
obesogenic diets
Pharmacotherapies that target the glucagon-like peptide 1 receptor (GLP-1R) system are commonly prescribed
for the treatment of type II diabetes and, more recently, for weight loss. Although successful at reducing appetite
and bodyweight, there are several limitations of GLP-1R agonists that limit their widespread use. Moreover, the
role of the endogenous GLP-1 and GLP-1R system, particularly in the brain, and its role in obesity pathogenesis
is unclear. In this application, our multidisciplinary team will address this primary gap in knowledge by dissecting
the function and activity states of GLP-1-producing neurons in the nucleus of the solitary tract (NTS) and their
outputs to GLP-1R-expressing neurons in the paraventricular nucleus of the hypothalamus (PVH) in a model of
diet-induced obesity. In Aim 1, we will use convergent electrophysiological, anatomical, and optical methods to
measure the wiring and activity states of GcgNTS neurons, the primary source of GLP-1 in the brain, after
exposure to obesogenic high fat diet. Further, we will use custom tools and novel transgenic mice to dissect
neurotransmission between GcgNTS neurons and one of their primary outputs in the PVH, Glp1rPVH neurons, ex
vivo and in vivo. In Aim 2, we will determine the causal role of GcgNTS neurons and outputs to the PVH in
progressive and interventional models of diet-induced obesity using intersectional viral tools. These exciting
experiments will yield important insight into the pathophysiological role of the brain’s endogenous GLP-1/GLP-
1R system and establish if targeting GcgNTS neurons is a therapeutically tractable strategy for new obesity
treatments.

## Key facts

- **NIH application ID:** 10945549
- **Project number:** 1R01DK140308-01
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** James Andrew Hardaway
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $655,971
- **Award type:** 1
- **Project period:** 2024-08-05 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10945549

## Citation

> US National Institutes of Health, RePORTER application 10945549, Pathophysiological mechanisms in the brain's endogenous glucagon-like peptide 1 system mediated by obesogenic diets (1R01DK140308-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10945549. Licensed CC0.

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