# Examining the role of locus coeruleus glucagon-like peptide-1 receptors in feeding behavior

> **NIH NIH K01** · UNIVERSITY OF PENNSYLVANIA · 2024 · $153,846

## Abstract

Project Summary/Abstract
The staggering prevalence of obesity presents major public health and economic consequences. Effective anti-
obesity drugs are desperately needed to combat the obesity epidemic, as behavioral strategies offer limited
success. Analogs of the endogenous satiety signal glucagon-like peptide-1 (GLP-1) suppress food intake and
body weight and are FDA-approved for obesity treatment. However, GLP-1 analogs (e.g. semaglutide) are
burdened by side effects, namely nausea and emesis. Therefore, increasing the therapeutic potential of GLP-1
receptor (GLP-1R) agonists requires characterization of the central mechanisms that mediate both the food
intake-suppressive and nausea/emesis effects of GLP-1. Preliminary data in the rat indicate that GLP-1Rs in
the locus coeruleus (LC), a source of norepinephrine (NE) output in the brain, are pharmacologically and
physiologically relevant for the food intake and illness-like effects of GLP-1. However, the circuit by which
endogenous GLP-1 signaling in the LC contributes to food intake suppression and nausea/emesis remains
unclear. Additionally, the functional relevance of LC GLP-1Rs to the food intake suppressive and
nausea/emesis effects of the semaglutide is not known.
The main goal of the proposed 5- year research career development plan is to facilitate the applicant’s
transition to a tenure-track Assistant Professor with independent R01 funding. To this end, the proposed
research will train the applicant in a variety of approaches to identify the behavioral, cellular, and circuit-level
mechanisms behind LC GLP-1R induced anorexia and illness-like behaviors. Aim I will utilize pharmacological,
chemogenetic and RNAi-mediated GLP-1R knockdown strategies in the rat and musk shrew, a preclinical
model that has an emetic profile similar to humans, to reveal a circuit by which endogenous GLP-1 signaling in
the LC contributes to food intake suppression, nausea and emesis. Aim II will take a translational approach by
determining the real-time calcium signaling dynamics of LC NE neurons to semaglutide as well as the
pharmacological relevance of LC GLP-1Rs to the food intake suppression, nausea/emesis and calcium signaling
evoked by systemic semaglutide. Aim II will use also cutting-edge single nucleus RNA sequencing and
bioinformatic analysis to probe semaglutide-induced changes in the LC NE neuron transcriptome to reveal the
fingerprint of LC neurons and regulation of LC NE neuron genes by semaglutide. Results from these
experiments will inform the development of more efficacious and tolerated obesity treatments and will provide
the applicant with a unique set of skills and pilot data to encourage her transition to research independence.

## Key facts

- **NIH application ID:** 10806181
- **Project number:** 5K01DK133627-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Samantha Fortin
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $153,846
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10806181

## Citation

> US National Institutes of Health, RePORTER application 10806181, Examining the role of locus coeruleus glucagon-like peptide-1 receptors in feeding behavior (5K01DK133627-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10806181. Licensed CC0.

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