Sympathetic Function in Human Carriers of Melanocortin-4 Receptor Gene Mutations
Abstract
CONTEXT: Melanocortinergic pathways clearly appear to be involved in obesity-associated sympathetic overactivity and its hemodynamic and thermoregulatory consequences. Individuals with dysfunctional mutations in the melanocortin-4 receptor gene (MC4R) are subject to obesity without developing hypertension. OBJECTIVE: This study aimed at characterizing the impact of the MC4R on sympathetic nerve traffic relevant to the cardiovascular system in humans. PARTICIPANTS: Participants included eight heterozygous carriers of MC4R mutations leading to a reduced function and control subjects matched for gender, age, and body mass index. MEASUREMENTS: We investigated vasoconstrictive muscle sympathetic nerve activity (MSNA), a direct measure of central sympathetic nervous outflow. MSNA was recorded microneurographically from the peroneal nerve at supine rest and during apnea-induced sympathoexcitation. Sympathetic activity was correlated with serum leptin levels and hemodynamic and anthropometric data. RESULTS: Individuals with MC4R impairment due to functional MC4R mutations were characterized by an inverse correlation between MSNA with body mass index and leptin levels, with the most obese subjects having the lowest MSNA. Resting MSNA, diastolic blood pressure, and heart rate tended to be lower in MC4R mutation carriers, and stimulated MSNA during apnea was significantly lower as compared with control subjects. CONCLUSION: The fact that obese subjects with MC4R mutations show an inverse relationship between obesity and MSNA suggests that central sympathetic outflow to the vasculature might depend on functional melanocortinergic pathways. Their dysfunction could explain reduced sympathoexcitability, lower sympathetic nerve-induced lipolysis, and the fact that blood pressure is rarely elevated in this type of obesity.
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Patients with obesity and MC4R mutations showed a substantial reduction in apnoea-induced increases in muscle sympathetic nerve activity compared with control individuals with obesity and intact MC4R signalling.
“Moreover, patients with obesity and MC4R mutations showed a substantial reduction in apnoea-induced increases in MSNA compared with control individuals with obesity and intact MC4R signalling206.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [206]
Individuals with MC4R mutations exhibit impaired sympathetic nervous system responses to a hypoxia stress test.
“In additon, individuals with MC4R mutations exhibit reduced muscle SNS activity and impaired SNS responses to a hypoxia stress test [55].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [55]
Individuals with MC4R mutations exhibit reduced muscle sympathetic nervous system activity.
“In additon, individuals with MC4R mutations exhibit reduced muscle SNS activity and impaired SNS responses to a hypoxia stress test [55].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [55]
In obese humans and obese rodents functional MC4Rs may be required for normal sympathetic responses to acute stress as well as increases in sympathetic nervous system activity and blood pressure.
“These observations suggest that in obese humans and obese rodents functional MC4Rs may be required for normal sympathetic responses to acute stress as well as increases in SNS activity and BP.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [55]
The brain melanocortin pathway is crucial in the regulation of sympathetic activity and blood pressure in obesity.
“The brain melanocortin pathway has emerged from studies in both experimental animals74,75 and humans89,90 as a crucial pathway in the regulation of sympathetic activity and BP in obesity.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [90]
Rare patients with obesity caused by loss of function mutations in hypothalamic melanocortin-4 receptors have lower sympathetic activity and blood pressure than control, weight-matched patients with common human obesity.
“These individuals have lower sympathetic activity and blood pressure than control, weight-matched patients with common human obesity89,90.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [90]
Patients carrying loss-of-function mutations in MC4R were found to be protected from obesity-associated elevation in blood pressure, heart rate and sympathetic tone.
“Patients carrying loss-of-function mutations in MC4R were found to be protected from obesity-associated elevation in blood pressure, heart rate and sympathetic tone (36;37).”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [37]
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- Authors
- Sayk, F., Heutling, D., Dodt, C., Iwen, K. A., Wellhoner, J. P., Scherag, S., Hinney, A., Hebebrand, J., & Lehnert, H.
- Affiliations
- University Hospital Schleswig-Holstein (DE)
- Otto-von-Guericke-Universität Magdeburg (DE)
- München Klinik Bogenhausen (DE)
- University of Duisburg-Essen (DE)
- University Hospital Coventry (GB)
- Corresponding author
- Lehnert, Hendrik
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2010-04-01
- Volume
- 95
- Issue
- 4
- Pages
- 1998-2002
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2118266265
- Cited by
- 86
- References
- 20
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2023: 2 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 7 · 2018: 3 · 2017: 8 · 2016: 4 · 2015: 5 · 2014: 7 · 2013: 13 · 2012: 4
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- melanocortin-4 receptor, MC4R mutations, muscle sympathetic nerve activity, sympathetic nervous system, obesity, leptin, body mass index, blood pressure, heart rate
- MeSH terms
- Adolescent, Adult, Anthropometry, Apnea, Blood Pressure, Child, Female, Heart Rate, Hemodynamics, Heterozygote, Humans, Male, Middle Aged, Mutation, Obesity, Regression Analysis, Sympathetic Nervous System, Muscle, Skeletal, Receptor, Melanocortin, Type 4, Young Adult
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