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

> **NIH NIH F32** · UNIVERSITY OF PENNSYLVANIA · 2020 · $70,146

## 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 energy balance control by reducing food intake
and increasing energy expenditure 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 amplifies NTS neural signaling, food intake and body weight
suppression and energy expenditure increases 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 and energy expenditure, we expect
NTS delivered MTII to also enhance energy expenditure as well as 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 cre-recombinase delivered to either the nodose ganglion of the vagus nerve or to the NTS of MC4Rlox/lox
mice to selectively knockdown MC4Rs expressed on vagal presynaptic afferents or postsynaptic NTS neurons,
respectively. We will analyze feeding behavior and energy expenditure in each of these groups of mice to
dissociate the endogenous contribution of pre- and postsynaptic NTS MC4Rs to food intake, energy expenditure
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 and energy expenditure-enhancing 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:** 10014592
- **Project number:** 5F32DK120211-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Samantha Fortin
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $70,146
- **Award type:** 5
- **Project period:** 2019-06-15 → 2021-12-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10014592

## Citation

> US National Institutes of Health, RePORTER application 10014592, Amplification of satiation signaling by melanocortin-4 receptors in the nucleus tractus solitarius (5F32DK120211-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10014592. Licensed CC0.

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