# Amplification of satiation signaling by melanocortin-4 receptors in the nucleus tractus solitarius

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2021 · $2,500

## Abstract

Project Summary
The astounding prevalence of obesity presents major public health and economic consequences. The
development of more effective therapeutics for weight loss is paramount and requires basic science research to
characterize the neural control of feeding behavior. Melanocortin signaling, through melanocortin 4 receptors
(MC4Rs) in the nucleus tractus solitarius (NTS) contributes to food intake control by reducing meal size via
amplification of within-meal gastrointestinally (GI)-derived satiation signals. However, the mechanism of MC4R
signaling within the NTS is not clear and the translational significance of the interaction between NTS
melanocortin signaling and other hormonal systems at the level of the NTS has not been adequately explored.
The proposed research aims to test the hypothesis that endogenous pre- and postsynaptic NTS MC4R
activity modulates NTS neural signaling and food intake and body weight suppression evoked by the GI-
derived satiation signals cholecystokinin (CCK) and glucagon-like peptide-1 (GLP-1). Specific Aim I will
use in vivo fiber photometry to examine bidirectional modulation of CCK- and GLP-1-evoked NTS neural activity
by hindbrain delivery of the MC4R agonist MTII or antagonist Shu9119. We hypothesize that neural activity
evoked by either of these satiation signals will be amplified by exogenous MTII and attenuated by Shu9119. As
we hypothesize that potentiation of NTS neural activity will result in amplified satiation signaling, we expect NTS
delivered MTII to also enhance the food intake and body weight suppressive effects of peripherally administered
CCK or GLP-1. Specific Aim II will utilize an adeno-associated virus (AAV)-encoding a validated shRNA construct
for the MC4R, delivered to either the nodose ganglion of the vagus nerve or to the NTS, to selectively knockdown
MC4Rs expressed on vagal presynaptic afferents or postsynaptic NTS neurons, respectively. We will analyze
day-to-day meal patterns in each of these groups of rats to dissociate the endogenous contribution of pre- and
postsynaptic NTS MC4Rs to food intake and body weight control. We will go on to use this strategy to examine
the role of pre- and postsynaptic MC4Rs in mediating the intake-suppressive effects of exogenous NTS MTII
delivery and in potentiating the anorectic actions of CCK and GLP-1. Finally, we will begin to characterize the
phenotype of MTII-activated neurons within the NTS. By determining the functional relevance and mechanism
of MC4R signaling within the NTS, these studies will contribute to identification of a novel NTS MC4R-activated
circuit that may be manipulated through pharmacological approaches to reduce food intake and body weight.

## Key facts

- **NIH application ID:** 10389570
- **Project number:** 3F32DK120211-02S2
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Samantha Fortin
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $2,500
- **Award type:** 3
- **Project period:** 2019-06-15 → 2021-12-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10389570

## Citation

> US National Institutes of Health, RePORTER application 10389570, Amplification of satiation signaling by melanocortin-4 receptors in the nucleus tractus solitarius (3F32DK120211-02S2). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10389570. Licensed CC0.

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