Sympathetic Response to Insulin Is Mediated by Melanocortin 3/4 Receptors in the Hypothalamic Paraventricular Nucleus
Open accessAbstract
Hyperinsulinemia increases sympathetic nerve activity and contributes to cardiovascular dysfunction in obesity and diabetes. Neurons of the hypothalamic paraventricular nucleus (PVN) regulate sympathetic nerve activity through mono- and poly-synaptic connections to preganglionic neurons in the spinal cord. The purpose of the present study was to determine whether PVN neurons mediate the sympathetic response to insulin. Hyperinsulinemic-euglycemic clamps were performed in α-chloralose-anesthetized, male Sprague-Dawley rats (280–420 g) by an infusion of insulin (3.75 mU/kg per min) and 50% dextrose (0.75–2.0 mL/h) for 120 minutes. At 90 minutes, insulin significantly increased lumbar sympathetic nerve activity without any change in renal sympathetic nerve activity, heart rate, or blood glucose levels. Inhibition of the PVN with bilateral injection of the GABA A receptor agonist muscimol completely reversed the sympathoexcitatory response. However, direct injection of insulin into the PVN did not alter lumbar sympathetic nerve activity, and thereby suggests that insulin activates neurons upstream of the PVN. Interestingly, the sympathetic response to insulin was eliminated by PVN injection of the melanocortin 3/4 receptor antagonist SHU9119, but was unaffected by the angiotensin II type 1 receptor antagonist losartan. A final set of experiments suggests activation of PVN neurons during hyperinsulinemia increases glutamatergic drive to the rostral ventrolateral medulla. Collectively, these findings indicate that insulin activates a melanocortin-dependent pathway to the PVN that increases glutamatergic drive to the rostral ventrolateral medulla and alters cardiovascular function.
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In obese Zucker rats, central nervous system blockade of MC4R attenuated the sympathetic response to insulin.
“In obese Zucker rats, which exhibit defective LepR signalling, CNS blockade of MC4R reduced BP201 and attenuated the sympathetic response to insulin, suggesting that insulin might also activate POMC neurons202.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [202]
Insulin might also activate POMC neurons.
“In obese Zucker rats, which exhibit defective LepR signalling, CNS blockade of MC4R reduced BP201 and attenuated the sympathetic response to insulin, suggesting that insulin might also activate POMC neurons202.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [202]
The effect of hyperinsulinemia to acutely raise lumbar sympathetic nervous system activity was prevented by blockade of MC4R in the paraventricular nucleus.
“Previous acute experiments in anesthetized animals showed that microinjection of an MC4R agonist into the PVN increased RSNA and BP [18], and the effect of hyperinsulinemia to acutely raise lumbar SNS activity was prevented by blockade of MC4R in the PVN [37].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [37]
The melanocortin system has a powerful influence on energy homeostasis and is critically involved in mediating the metabolic, sympathetic and cardiovascular effects of leptin and insulin.
“The melanocortin system has a powerful influence on energy homeostasis and is critically involved in mediating the metabolic, sympathetic and cardiovascular effects of leptin and insulin (32–35).”
From Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis (2014) · cites this paper as [35]
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- Authors
- Ward, K. R., Bardgett, J. F., Wolfgang, L., & Stocker, S. D.
- Affiliations
- Pennsylvania State University (US)
- ORCID
- Stocker, Sean D.
- Venue
- Hypertension
- Published
- 2011-03
- Volume
- 57
- Issue
- 3
- Pages
- 435-441
- ISSN
- 0194-911X (ISSN-L)
- 1524-4563
- PMC
- PMC3580160
- OpenAlex
- W2166300547
- Cited by
- 118
- References
- 48
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 2 · 2022: 5 · 2021: 12 · 2020: 9 · 2019: 9 · 2018: 1 · 2017: 8 · 2016: 5 · 2015: 11 · 2014: 16 · 2013: 11 · 2012: 13
- FWCI
- 6.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hypertension (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-090826, R01HL090826)
- 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
- insulin, sympathetic activity, melanocortin 3/4 receptor, hypothalamic paraventricular nucleus, hyperinsulinemia, lumbar sympathetic nerve activity, muscimol, SHU9119, losartan, angiotensin II type 1 receptor, rostral ventrolateral medulla, cardiovascular dysfunction, obesity, diabetes mellitus
- MeSH terms
- Analysis of Variance, Animals, Blood Pressure, Glucose, Heart Rate, Insulin, Male, Medulla Oblongata, Muscimol, Neurons, Paraventricular Hypothalamic Nucleus, Sympathetic Nervous System, Glucose Clamp Technique, Rats, Sprague-Dawley, Losartan, Receptor, Melanocortin, Type 3, Receptor, Melanocortin, Type 4, Rats, Angiotensin Receptor Antagonists, GABA-A Receptor Agonists
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