Melanocortin-4 Receptor Mediates Chronic Cardiovascular and Metabolic Actions of Leptin
Abstract
This study tested whether the melanocortin 4-receptor (MC4R) is essential for the chronic cardiovascular and metabolic actions of leptin. Twenty- to 22-week–old male wild-type (WT) C57BL/6J and obese MC4R (−/−) mice (N=5 to 6 per group) were implanted with radiotelemetric transmitters and catheters for measuring mean arterial pressure (MAP) and heart rate 24 hours per day and intravenous infusions. After a 3-day stable control period, leptin was infused (2 μg/kg per minute IV) for 7 days in WT, obese ad libitum–fed MC4R (−/−), and nonobese pair–fed MC4R (−/−) mice. WT mice receiving vehicle for 7 days served as controls. MC4 (−/−) mice were 30% heavier and had 4- and 11-fold increases in plasma insulin and leptin levels, respectively, compared with WT mice. Despite obesity, MAP and heart rate tended to be lower in MC4R (−/−) mice compared with WT mice. Chronic leptin infusion in the different groups increased plasma leptin levels to 45 to 65 ng/mL. Seven-day leptin infusion in WT mice increased MAP by 12±3 mm Hg despite a 35% reduction in food intake and an 8% reduction in body weight. Leptin did not alter plasma glucose but reduced plasma insulin in WT mice (5.9±1.0 versus 3.0±0.5 μU/mL). These cardiovascular and metabolic actions of leptin were abolished in obese and nonobese MC4R (−/−) mice. These data suggest that MC4R deficiency, and not obesity-induced leptin resistance, abolished the cardiovascular and metabolic actions of leptin in obese MC4R (−/−) mice. Thus, a functional MC4R is essential for the chronic cardiovascular and metabolic actions of leptin.
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Mice with genetic disruption of MC4R signalling exhibit early-onset obesity, hyperphagia, insulin resistance, dyslipidaemia and other features of metabolic syndrome but have normal or reduced blood pressure even when fed high-salt diets.
“Mice with genetic disruption of MC4R signalling exhibit early-onset obesity, hyperphagia, insulin resistance, dyslipidaemia and other features of metabolic syndrome but have normal or reduced BP even when fed high-salt diets198.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [198]
MC4R appears to be the dominant efferent arm of the actions of the brain melanocortin system on regulation of food intake and body weight.
“Also, MC4R appears to be the dominant efferent arm of the actions of the brain melanocortin system on regulation of food intake and body weight [27, 28].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [27]
Leptin requires functional MC4R for most of its chronic cardiovascular and metabolic effects.
“Leptin requires functional MC4R for most of its chronic cardiovascular and metabolic effects.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [27]
Mice with whole-body MC4R deficiency are hyperphagic and obese, and have many characteristics of the metabolic syndrome including hyperglycemia, hyperinsulinemia, visceral adiposity and dyslipidemia despite markedly elevated blood leptin levels.
“Mice with whole-body MC4R deficiency are hyperphagic and obese, and have many characteristics of the metabolic syndrome including hyperglycemia, hyperinsulinemia, visceral adiposity and dyslipidemia despite markedly elevated blood leptin levels [27, 28, 52]; moreover, these mice are completely unresponsive to the effects of leptin to reduce appetite and to raise BP [27].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [27]
Mice with whole-body MC4R deficiency are completely unresponsive to the effects of leptin to reduce appetite and to raise blood pressure.
“Mice with whole-body MC4R deficiency are hyperphagic and obese, and have many characteristics of the metabolic syndrome including hyperglycemia, hyperinsulinemia, visceral adiposity and dyslipidemia despite markedly elevated blood leptin levels [27, 28, 52]; moreover, these mice are completely unresponsive to the effects of leptin to reduce appetite and to raise BP [27].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [27]
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Self-citation
- Authors
- Tallam, L. S., da Silva, A. A., & Hall, J. E.
- Affiliations
- University of Mississippi Medical Center (US)
- From the Department of Physiology, School of Medicine, University of Mississippi Medical Center, Jackson, Miss.
- ORCID
- Hall, John E.
- Venue
- Hypertension
- Published
- 2006-07
- Volume
- 48
- Issue
- 1
- Pages
- 58-64
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2145600837
- Cited by
- 133
- References
- 41
- Citations by year
- 2026: 5 · 2025: 4 · 2024: 1 · 2023: 3 · 2021: 3 · 2020: 5 · 2019: 3 · 2018: 6 · 2017: 10 · 2016: 8 · 2015: 9 · 2014: 9 · 2013: 12 · 2012: 8
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01HL051971)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- melanocortin-4 receptor, leptin, leptin resistance, obesity, mean arterial pressure, heart rate, insulin
- MeSH terms
- Analysis of Variance, Animals, Blood Glucose, Blood Pressure, Body Weight, Eating, Glomerular Filtration Rate, Heart Rate, Insulin, Male, Mice, Inbred C57BL, Mice, Obese, Leptin, Receptor, Melanocortin, Type 4, Adiposity, Mice, Receptors, Leptin
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