Modulation of Blood Pressure by Central Melanocortinergic Pathways
Open accessAbstract
BACKGROUND: Weight gain and weight loss are associated with changes in blood pressure through unknown mechanisms. Central melanocortinergic signaling is implicated in the control of energy balance and blood pressure in rodents, but there is no information regarding such an association with blood pressure in humans. METHODS: We assessed blood pressure, heart rate, and urinary catecholamines in overweight or obese subjects with a loss-of-function mutation in MC4R, the gene encoding the melanocortin 4 receptor, and in equally overweight control subjects. We also examined the effects of an MC4R agonist administered for 7 days in 28 overweight or obese volunteers. RESULTS: The prevalence of hypertension was markedly lower in the MC4R-deficient subjects than in the control subjects (24% vs. 53%, P=0.009). After the exclusion of subjects taking antihypertensive medications, blood-pressure levels were significantly lower in MC4R-deficient subjects than in control subjects, with mean (+/-SE) systolic blood pressures of 123+/-14 mm Hg and 131+/-12 mm Hg, respectively (P=0.02), and mean diastolic blood pressures of 73+/-10 mm Hg and 79+/-7 mm Hg, respectively (P=0.03). As compared with control subjects, MC4R-deficient subjects had a lower increase in heart rate on waking (P=0.007), a lower heart rate during euglycemic hyperinsulinemia (P<0.001), and lower 24-hour urinary norepinephrine excretion (P=0.04). The maximum tolerated daily dose of 1.0 mg of the MC4R agonist led to significant increases of 9.3+/-1.9 mm Hg in systolic blood pressure and of 6.6+/-1.1 mm Hg in diastolic blood pressure (P<0.001 for both comparisons) at 24 hours, as compared with placebo. Differences in blood pressure were not explained by changes in insulin levels; there were no significant adverse events. CONCLUSIONS: Results of our genetic and pharmacologic studies implicate melanocortinergic signaling in the control of human blood pressure through an insulin-independent mechanism.
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Treatment with synthetic MC4R agonists raises blood pressure and heart rate despite causing weight loss in people with obesity.
“Similar to their effects in rodents, treatment with synthetic MC4R agonists raises BP and HR despite causing weight loss in people with obesity; these effects limit the use of MC4R agonists in the treatment of obesity199.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [199]
These effects limit the use of MC4R agonists in the treatment of obesity.
“Similar to their effects in rodents, treatment with synthetic MC4R agonists raises BP and HR despite causing weight loss in people with obesity; these effects limit the use of MC4R agonists in the treatment of obesity199.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [199]
Compared with control individuals with obesity and intact MC4R signalling, individuals with MC4R deficiency had a lower prevalence of hypertension and reduced noradrenaline excretion despite severe obesity, insulin resistance and dyslipidemia.
“Compared with control individuals with obesity and intact MC4R signalling, individuals with MC4R deficiency had a lower prevalence of hypertension and reduced noradrenaline excretion despite severe obesity, insulin resistance and dyslipidemia199,200.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [199]
Hypertension prevalence is lower in MC4R deficient humans compared to control subjects, despite severe obesity and associated metabolic disorders.
“Hypertension prevalence is lower in MC4R deficient humans compared to control subjects, despite severe obesity and associated metabolic disorders125,126.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [126]
The cardiovascular effects of LY2112688 were sustained for the entire 7 days of infusion.
“Moreover, the cardiovascular effects were sustained for the entire 7 days of LY2112688 infusion.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [77]
LY2112688, a selective MC4R agonist, caused dose-dependent increases in blood pressure during peripheral infusion for 24 hours in overweight or obese adults.
“Studies by Greenfield et al. [77] demonstrated that LY2112688, a selective MC4R agonist, caused dose-dependent increases in BP and HR during peripheral infusion for 24 hours in overweight or obese adults.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [77]
LY2112688 caused dose-dependent increases in heart rate during peripheral infusion for 24 hours in overweight or obese adults.
“Studies by Greenfield et al. [77] demonstrated that LY2112688, a selective MC4R agonist, caused dose-dependent increases in BP and HR during peripheral infusion for 24 hours in overweight or obese adults.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [77]
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 [89]
Administration of a hypothalamic melanocortin-4 receptor agonist in healthy subjects increases blood pressure.
“In addition, administration of an hypothalamic melanocortin-4 receptors agonist in healthy subjects increases blood pressure89.”
From The Sympathetic Nervous System Alterations in Human Hypertension (2015) · cites this paper as [89]
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 [89]
Stimulation of the MC4R led to significant and dose-dependent increase in blood pressure in healthy overweight or obese subjects.
“Conversely, stimulation of the MC4R led to significant and dose-dependent increase in blood pressure in healthy overweight or obese subjects (36).”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [36]
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 [36]
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- Authors
- Greenfield, J. R., Miller, J. W., Keogh, J. M., Henning, E., Satterwhite, J. H., Cameron, G. S., Astruc, B., Mayer, J. P., Brage, S., See, T. C., Lomas, D. J., O'Rahilly, S., & Farooqi, I. S.
- Affiliations
- University of Cambridge (GB)
- Eli Lilly (United States) (US)
- Biotrial (France) (FR)
- Addenbrooke's Hospital (GB)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2009-01
- Volume
- 360
- Issue
- 1
- Pages
- 44-52
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W3144014357
- Cited by
- 477
- References
- 29
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 26 · 2023: 9 · 2022: 29 · 2021: 36 · 2020: 26 · 2019: 21 · 2018: 19 · 2017: 30 · 2016: 33 · 2015: 32 · 2014: 34 · 2013: 38 · 2012: 22
- FWCI
- 13.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (082390)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- blood pressure regulation, melanocortin signaling, melanocortin-4 receptor, MC4R agonist, obesity, overweight, hypertension, heart rate, urinary catecholamines, norepinephrine, energy balance
- MeSH terms
- Adult, Autonomic Nervous System, Blood Pressure, Catecholamines, Dose-Response Relationship, Drug, Double-Blind Method, Female, Genotype, Heart Rate, Heterozygote, Humans, Hypertension, Male, Mutation, Obesity, Sleep, Signal Transduction, Prevalence, Cross-Over Studies, Receptor, Melanocortin, Type 4, Overweight
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