# Melanocortin 4 signaling in the carotid body in obesity

> **NIH NIH R01** · GEORGE WASHINGTON UNIVERSITY · 2024 · $204,887

## Abstract

This application is submitted in response to the PA-23-189 Research Supplements to Promote Diversity in
Health-Related Research (Admin Supp - Clinical Trial Not Allowed). The parent grant is ‘Leptin signaling in the
carotid body: mechanisms and consequences’, R01HL133100-7, 04/01/2023 – 03/31/2025 with contact PI
Vsevolod Y Polotsky, MD, PhD. Obesity is a major health problem leading to high cardiovascular morbidity and
mortality Main complications of obesity are hypertension and sleep disordered breathing (SDB), which greatly
contribute to obesity-related morbidity and mortality. Our parent grant is focused on mechanisms by which
obesity acts on the carotid body (CB), a key sensor of hypoxia and multiple metabolic parameters, to cause
hypertension and SDB. In our parent grant we have shown that an adipocyte produced hormone leptin acts on
the long isoform of leptin receptor (LEPRb) in the CB glomus (Type I) cells to increase carotid sinus nerve (CSN)
activity leading to hypertension. LEPRb signaling in the CB causes transcriptional and post-transcriptional
activation of TRPM7, which is responsible for both respiratory and cardiovascular effects of leptin in CB.
However, leptin may act on the CB via alternative pathways. Leptin upregulates pro-opiomelanocortin (POMC),
which is a pre-hormone post-transcriptionally processed into several peptides, including α-melanocyte
stimulating hormone (α-MSH), a ligand for the melanocortin 4 receptor (MC4R). MC4R deficiency prevents the
development of hypertension in obesity. MC4R has been implicated in the developing of hypertension in SDB
Our Preliminary Data show that CIH leads to a striking increase in Mc4r expression in CB. Of note, Trpm7
knockdown in the CB appeared to attenuate the effect of IH on Mc4r expression, which suggests that MC4R is
downstream of leptin-TRPM7 signaling. However, the role of CB MC4R in obesity and SDB related hypertension
is unknown. The overarching hypothesis of this proposal is that, DIO and SDB act via MC4R in the CB to
increase carotid sinus nerve (CSN) activity and hypoxic chemoreflex leading to hypertension and SDB,
all of which can be attenuated by Mc4r shRNA administered to the CB. Specific Aim 1 will examine the
role of MC4R in CB in DIO- and CIH- induced hypertension and potential implications for therapy. We propose
that DIO and CIH increase MC4R expression in CB, carotid sinus nerve (CSN) and sympathetic nerve (SNS)
activity and blood pressure, which will be attenuated by Mc4r shRNA applied to CB. Specific Aim 2 will examine
the role of MC4R in CB in DIO-induced SDB and potential implications for therapy. We propose that DIO
increases MC4R signaling in CB, which augments chemoreflex, destabilizes breathing and exacerbates SDB,
and that Mc4r shRNA applied to CB will decrease hypoxic chemoreflex and attenuate SDB. The Candidate, Dr.
Mateus Amorim will work on this proposal paving a way to his future career as an independent investigator.

## Key facts

- **NIH application ID:** 10975638
- **Project number:** 3R01HL133100-08S1
- **Recipient organization:** GEORGE WASHINGTON UNIVERSITY
- **Principal Investigator:** Vsevolod Y Polotsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $204,887
- **Award type:** 3
- **Project period:** 2023-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975638

## Citation

> US National Institutes of Health, RePORTER application 10975638, Melanocortin 4 signaling in the carotid body in obesity (3R01HL133100-08S1). Retrieved via AI Analytics 2026-06-08 from https://api.ai-analytics.org/grant/nih/10975638. Licensed CC0.

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