Role of hypothalamic melanocortin 3/4-receptors in mediating chronic cardiovascular, renal, and metabolic actions of leptin
Abstract
The present study examined whether blockade of melanocortin receptors subtypes 3 and 4 (MC3/4-R) inhibits chronic cardiovascular and dietary responses to leptin infusion. A cannula was placed in the lateral ventricle of male Sprague-Dawley rats for chronic intracerebroventricular (ICV) infusion via osmotic minipump, and arterial and venous catheters were implanted for measurement of mean arterial pressure (MAP) and heart rate (HR) 24 h/d and IV infusions. After a 5-day control period, rats received (1) 0.9% saline vehicle ICV for 12 days plus leptin (1 microg/kg per minute IV, n=5) during the final 7 days; (2) MC3/4-R antagonist SHU-9119 (1 nmol/h ICV) for 12 days plus leptin (1 microg/kg per minute IV, n=6) during the final 7 days; and (3) SHU-9119 (1 nmol/h ICV, n=8) for 12 days. Leptin infusion in vehicle-treated rats caused a small increase in MAP (5+/-1 mm Hg) despite reduced food intake (23+/-1 to 10+/-1 g/d) and decreased body weight (-6%+/-1%). SHU-9119 infusion completely prevented the cardiovascular and dietary actions of leptin, leading to increased food intake (23+/-1 to 49+/-4 g/d) and body weight (+30%+/-2%), markedly decreased HR (-77+/-9 bpm), and caused a decrease in MAP (-6+/-1 mm Hg). Similar results were observed when SHU-9119 was infused alone in vehicle-treated rats. Leptin decreased plasma insulin to 30% of control values, an effect that was also abolished by SHU-9119 treatment, which caused a 5-fold increase in plasma insulin concentration. Thus, MC3/4-R antagonism completely blocked the chronic cardiovascular, satiety, and metabolic effects of leptin, suggesting that the hypothalamic melanocortin system plays an important role in mediating these actions of leptin.
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In lean normotensive animals, chronic MC4R antagonism caused sustained bradycardia and reduced blood pressure in spite of hyperphagia and rapid weight gain.
“In lean normotensive animals, chronic MC4R antagonism caused sustained bradycardia and reduced BP in spite of hyperphagia and rapid weight gain which normally would evoke tachycardia and elevated BP [56].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [56]
Blockade of central nervous system MC4R for 12 consecutive days caused a much greater reduction in blood pressure in spontaneously hypertensive rats than in normotensive Sprague-Dawley or Wistar-Kyoto rats despite causing marked hyperphagia, weight gain, and insulin resistance.
“Blockade of CNS MC4R for 12 consecutive days caused a much greater reduction in BP in SHR than in normotensive Sprague-Dawley or Wistar-Kyoto rats despite causing marked hyperphagia, weight gain, and insulin resistance [42, 56].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [56]
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- Authors
- da Silva, A. A., Kuo, J. J., & Hall, J. E.
- Affiliations
- From the University of Mississippi Medical Center, Jackson.
- University of Mississippi Medical Center (US)
- Venue
- Hypertension
- Published
- 2004-06
- Volume
- 43
- Issue
- 6
- Pages
- 1312-1317
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- OpenAlex
- W2134934076
- Cited by
- 117
- References
- 23
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 4 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 6 · 2014: 7 · 2013: 6 · 2012: 5
- FWCI
- 2.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (P01-HL-51971, P01HL051971)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- leptin, melanocortin 3/4 receptor, intracerebroventricular infusion, mean arterial pressure, heart rate, dietary intake, body weight, insulin, satiety
- MeSH terms
- Animals, Blood Pressure, Diuresis, Eating, Heart Rate, Hemodynamics, Hypothalamus, Insulin, Kidney, Male, Melanocyte-Stimulating Hormones, Natriuresis, Renin, Satiety Response, Weight Gain, Infusion Pumps, Implantable, Rats, Sprague-Dawley, Leptin, Receptor, Melanocortin, Type 3, Receptor, Melanocortin, Type 4, Rats
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