# Acute and chronic effects of GLP-1R agonism on NPY/AgRP neuronal activity

> **NIH NIH R56** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $410,000

## Abstract

Glucagon-like peptide 1 (GLP-1)-based therapeutics have profound effects on body weight and blood glucose management. GLP-1 cells are located in both the periphery and the caudal medulla, specifically within the nucleus tractus solitarius (NTS). However, the effects of GLP-1 or long-acting GLP-1 receptor agonists (GLP1Rags) on synaptic/cellular properties in the brain and their contribution to metabolic changes are not entirely understood. Based on pilot data, we hypothesize that a DMH GLP-1R → NPY/AgRP neuron circuit is a target for brain-derived GLP-1 neurons and GLP-1Rags. Our objective is to determine if DMH GLP-1R neurons are required for the NTS GLP-1-induced effects on NPY/AgRP activity and metabolism. The project will use 
chemogenetics, electrophysiology, and in-vivo calcium imaging to investigate these questions. These experiments will potentially bridge our understanding of the regulation and physiological roles of the GLP-1system in the brain and in the treatment of metabolic disease. 
Glucagon-like-peptide-1 receptor agonists (GLP-1Rags) have profound anti-diabetic and antiobesity effects, but the neural systems responsible for mediating these effects are not fully understood. The endogenous function of brain-derived GLP-1, located in the Nucleus Tractus Solitarius (NTS), may provide insight into the effects of GLP-1Rags in the brain. In particular, NTS GLP-1 neurons target multiple brain regions and reduce food intake and glucose production upon activation, which is similar to the effects of GLP-1Rags. While NTS GLP-1 neurons do not express GLP-1receptors, GLP-1Rags may activate target nuclei downstream of NTS GLP-1 neurons that do express GLP-1Rs, thereby mimicking the effects of stimulating NTS GLP-1 neurons. We hypothesize one component of the beneficial effects of both NTS GLP-1 and GLP-1Rags on metabolism involves an NTS GLP-1 neuron → dorsal medial nucleus of the hypothalamus (DMH) GABAergic neuron → Arcuate nucleus circuit that ultimately reduces Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neuron activity. This study aims to define this NTS → DMH → arcuate circuit and determine if GLP-1Rags and central GLP-1 converge on the DMH to inhibit NPY/AgRP neurons and improve metabolism. Previous work and preliminary data demonstrate that: 1) GLP1-Rags decrease the excitability of NPY/AgRP neurons, 2) a GABAergic neuron that expresses GLP-1Rs and leptin receptors (LepRs) resides in the DMH, 3) DMH GLP-1R+ and LepR+ neurons are activated by GLP-1Rags, food presentation/intake, and/or elevated glucose levels, and 4) there is synchrony in the regulation of activity of these neurons. Specifically, when NTS GLP-1 or DMH LepR+/GLP-1R+ neurons are activated, NPY/AgRP neurons are inhibited. These findings suggest the NTS GLP-1 → DMH GLP-1R/LepR → NPY/AgRP circuit functions as a convergence point for satiety signals. We aim to investigate the role of DMH GLP-1R+ neurons in mediating the effects of GLP-1Rags and NTS GLP-1 neuron activity, ...

## Key facts

- **NIH application ID:** 11133670
- **Project number:** 1R56DK135501-01A1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** KEVIN W WILLIAMS
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 1
- **Project period:** 2024-08-19 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11133670

## Citation

> US National Institutes of Health, RePORTER application 11133670, Acute and chronic effects of GLP-1R agonism on NPY/AgRP neuronal activity (1R56DK135501-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11133670. Licensed CC0.

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