The DOI matches its Crossref record; 49 of the 49 references it cites were found in a registry or an index.
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 the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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Cites
The sympathetic control of blood pressure
Guyenet, P. G. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1902 · Cited by 1,863
Hyperinsulinemia produces both sympathetic neural activation and vasodilation in normal humans.
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Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G., Baskin, D. G., & Rossetti, L. (2002) · Nature Neuroscience · doi:10.1038/nn0602-861 · Cited by 719
Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat
Kishi, T., Aschkenasi, C. J., Lee, C. E., Mountjoy, K. G., Saper, C. B., & Elmquist, J. K. (2003) · The Journal of Comparative Neurology · doi:10.1002/cne.10454 · Cited by 581
Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats
Obici, S., Feng, Z., Karkanias, G. B., et al. (2002) · Nature Neuroscience · doi:10.1038/nn861 · Cited by 572
Modulation of Blood Pressure by Central Melanocortinergic Pathways
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., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0803085 · Cited by 477
Localization of insulin receptor mRNA in rat brain by in situ hybridization
MARKS, J. L., PORTE, D., STAHL, W. L., & BASKIN, D. G. (1990) · Endocrinology · doi:10.1210/endo-127-6-3234 · Cited by 448
Mechanisms of Sympathetic Activation in Obesity-Related Hypertension
Esler, M., Straznicky, N., Eikelis, N., Masuo, K., Lambert, G., & Lambert, E. (2006) · Hypertension · doi:10.1161/01.hyp.0000242642.42177.49 · Cited by 443
The Catabolic Action of Insulin in the Brain Is Mediated by Melanocortins
Benoit, S. C., Air, E. L., Coolen, L. M., Strauss, R., Jackman, A., Clegg, D. J., Seeley, R. J., & Woods, S. C. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-20-09048.2002 · Cited by 417
Evidence for two separate opiate peptide neuronal systems
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Cited by
Sorted by citations
Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms
Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z., & Hall, M. E. (2015) · Circulation Research · doi:10.1161/circresaha.116.305697 · Cited by 1,360
Obesity, kidney dysfunction and hypertension: mechanistic links
Hall, J. E., do Carmo, J. M., da Silva, A. A., Wang, Z., & Hall, M. E. (2019) · Nature Reviews Nephrology · doi:10.1038/s41581-019-0145-4 · Cited by 654
Role of Hyperinsulinemia and Insulin Resistance in Hypertension: Metabolic Syndrome Revisited
da Silva, A. A., do Carmo, J. M., Li, X., Wang, Z., Mouton, A. J., & Hall, J. E. (2020) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2020.02.066 · Cited by 392
Shariq, O. A., & McKenzie, T. J. (2020) · Gland Surgery · doi:10.21037/gs.2019.12.03 · Cited by 427
Obesity-Associated Hypertension: Recent Progress in Deciphering the Pathogenesis
Rahmouni, K. (2014) · Hypertension · doi:10.1161/hypertensionaha.114.00920 · Cited by 150
Metadata
- 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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