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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
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.
Anderson, E. A., Hoffman, R. P., Balon, T. W., Sinkey, C. A., & Mark, A. L. (1991) · Journal of Clinical Investigation · doi:10.1172/jci115260 · Cited by 1,075
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
Watson, S., Akil, H., Richard, C. W., & Barchas, J. (1978) · Nature · doi:10.1038/275226a0 · Cited by 410
Regional Sympathetic Nervous Activity and Oxygen Consumption in Obese Normotensive Human Subjects
Vaz, M., Jennings, G., Turner, A., Cox, H., Lambert, G., & Esler, M. (1997) · Circulation · doi:10.1161/01.cir.96.10.3423 · Cited by 404
Body fat and sympathetic nerve activity in healthy subjects.
Scherrer, U., Randin, D., Tappy, L., Vollenweider, P., Jéquier, E., & Nicod, P. (1994) · Circulation · doi:10.1161/01.cir.89.6.2634 · Cited by 383
Acute effects of leptin require PI3K signaling in hypothalamic proopiomelanocortin neurons in mice
Hill, J. W., Williams, K. W., Ye, C., Luo, J., Balthasar, N., Coppari, R., Cowley, M. A., Cantley, L. C., Lowell, B. B., & Elmquist, J. K. (2008) · Journal of Clinical Investigation · doi:10.1172/jci32964 · Cited by 362
Interactions between the melanocortin system and leptin in control of sympathetic nerve traffic
Haynes, W. G., Morgan, D. A., Djalali, A., Sivitz, W. I., & Mark, A. L. (1999) · Hypertension · doi:10.1161/01.hyp.33.1.542 · Cited by 358
Williams, K. W., Margatho, L. O., Lee, C. E., Choi, M., Lee, S., Scott, M. M., Elias, C. F., & Elmquist, J. K. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.3118-09.2010 · Cited by 352
Werther, G. A., Hogg, A., Oldfield, B. J., McKinley, M. J., Figdor, R., Allen, A. M., & Mendelsohn, F. A. O. (1987) · Endocrinology · doi:10.1210/endo-121-4-1562 · Cited by 333
Landsberg, L. (2001) · Journal of Hypertension · doi:10.1097/00004872-200103001-00001 · Cited by 312
Mapping of angiotensin II receptor subtype heterogeneity in rat brain
Song, K., Allen, A. M., Paxinos, G., & Mendelsohn, F. A. O. (1992) · The Journal of Comparative Neurology · doi:10.1002/cne.903160407 · Cited by 302
Hypothalamic PI3K and MAPK differentially mediate regional sympathetic activation to insulin
Rahmouni, K., Morgan, D. A., Morgan, G. M., Liu, X., Sigmund, C. D., Mark, A. L., & Haynes, W. G. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21737 · Cited by 187
Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin
Rahmouni, K., Haynes, W. G., Morgan, D. A., & Mark, A. L. (2003) · The Journal of Neuroscience · doi:10.1523/jneurosci.23-14-05998.2003 · Cited by 185
Cardiovascular responses to bicuculline in the paraventricular nucleus of the rat.
Martin, D. S., Segura, T., & Haywood, J. R. (1991) · Hypertension · doi:10.1161/01.hyp.18.1.48 · Cited by 164
Tallam, L. S., Stec, D. E., Willis, M. A., da Silva, A. A., & Hall, J. E. (2005) · Hypertension · doi:10.1161/01.hyp.0000175474.99326.bf · Cited by 148
Palkovits, M., Mezey, É., & Eskay, R. L. (1987) · Brain Research · doi:10.1016/0006-8993(87)91676-3 · Cited by 142
Sympathetic nervous system activation by glutamate injections into the paraventricular nucleus
Martin, D. S., & Haywood, J. R. (1992) · Brain Research · doi:10.1016/0006-8993(92)90282-e · Cited by 141
Intracerebroventricular insulin produces nonuniform regional increases in sympathetic nerve activity
Muntzel, M. S., Morgan, D. A., Mark, A. L., & Johnson, A. K. (1994) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1994.267.5.r1350 · Cited by 134
Stocker, S. D., Simmons, J. R., Stornetta, R. L., Toney, G. M., & Guyenet, P. G. (2005) · The Journal of Comparative Neurology · doi:10.1002/cne.20835 · Cited by 130
Self-citationSubcutaneous obesity is not associated with sympathetic neural activation
Alvarez, G. E., Ballard, T. P., Beske, S. D., & Davy, K. P. (2004) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01046.2003 · Cited by 121
Chen, Q., Haywood, J. R., & Toney, G. M. (2003) · Hypertension · doi:10.1161/01.hyp.0000085197.20043.44 · Cited by 110
Young, C. N., Deo, S. H., Chaudhary, K. R., Thyfault, J. P., & Fadel, P. J. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.191866 · Cited by 102
Influence of Insulin in the Ventromedial Hypothalamus on Pancreatic Glucagon Secretion In Vivo
Paranjape, S., Chan, O. T. M., Zhu, W., Horblitt, A. M., McNay, E. C., Cresswell, J. A., Bogan, J. S., McCrimmon, R. J., & Sherwin, R. S. (2010) · Diabetes · doi:10.2337/db10-0014 · Cited by 98
The Hemodynamic Response to Chronic Hyperinsulinemia in Conscious Dogs
Brands, M. W., Mizelle, H. L., Gaillard, S., Hildebrandt, D. A., & Hall, J. E. (1991) · American Journal of Hypertension · doi:10.1093/ajh/4.2.164 · Cited by 96
Nonuniform regional sympathetic nerve responses to hyperinsulinemia in rats
Morgan, D. A., Balon, T. W., Ginsberg, B. H., & Mark, A. L. (1993) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1993.264.2.r423 · Cited by 92
Ward, K. D., Sparrow, D., Landsberg, L., Young, J. B., Vokonas, P. S., & Weiss, S. T. (1996) · Journal of Hypertension · doi:10.1097/00004872-199603000-00005 · Cited by 92
Self-citationModest weight gain is associated with sympathetic neural activation in nonobese humans
Gentile, C. L., Orr, J. S., Davy, B. M., & Davy, K. P. (2007) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00876.2006 · Cited by 92
Adams, J. M., Madden, C. J., Sved, A. F., & Stocker, S. D. (2007) · Hypertension · doi:10.1161/hypertensionaha.107.091843 · Cited by 82
Self-citationMonroe, M., Pelt, R. E. V., Schiller, B. C., Seals, D. R., & Jones, P. P. (2000) · International Journal of Obesity · doi:10.1038/sj.ijo.0801364 · Cited by 74
Lentivirus-mediated downregulation of hypothalamic insulin receptor expression
Grillo, C. A., Tamashiro, K. L., Piroli, G. G., Melhorn, S. J., Gass, J. T., Newsom, R. J., Reznikov, L. R., Smith, A. C., Wilson, S. P., Sakai, R. R., et al. (2007) · Physiology & Behavior · doi:10.1016/j.physbeh.2007.05.043 · Cited by 72
Bardgett, M. E., McCarthy, J. J., & Stocker, S. D. (2010) · Hypertension · doi:10.1161/hypertensionaha.109.146605 · Cited by 70
Self-citationDeering, J., & Coote, J. H. (2000) · Experimental Physiology · doi:10.1111/j.1469-445x.2000.01953.x · Cited by 70
Chen, Q., & Toney, G. M. (2003) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00028.2003 · Cited by 65
The role of glutamate and vasopressin in the excitation of RVL neurones by paraventricular neurones
Yang, Z. R., Bertram, D., & Coote, J. H. (2001) · Brain Research · doi:10.1016/s0006-8993(01)02593-8 · Cited by 61
Pricher, M. P., Freeman, K. L., & Brooks, V. L. (2007) · Hypertension · doi:10.1161/hypertensionaha.107.102608 · Cited by 58
Adams, J. M., McCarthy, J. J., & Stocker, S. D. (2008) · Hypertension · doi:10.1161/hypertensionaha.108.118935 · Cited by 56
Self-citationCardiac output and renal function during insulin hypertension in Sprague-Dawley rats
Brands, M. W., Lee, W. F., Keen, H. L., Alonso‐Galicia, M., Zappe, D. H., & Hall, J. E. (1996) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1996.271.1.r276 · Cited by 51
Anteroventral third ventricle lesions abolish lumbar sympathetic responses to insulin.
Muntzel, M., Beltz, T., Mark, A. L., & Johnson, A. K. (1994) · Hypertension · doi:10.1161/01.hyp.23.6.1059 · Cited by 48
Kawabe, T., Chitravanshi, V. C., Kawabe, K., & Sapru, H. N. (2006) · Brain Research · doi:10.1016/j.brainres.2006.05.002 · Cited by 26
Dubinion, J. H., da Silva, A. A., & Hall, J. E. (2010) · Journal of Hypertension · doi:10.1097/hjh.0b013e328339f20e · Cited by 25
Blockade of Angiotensin II Receptors Inhibits the Increase in Blood Pressure Induced by Insulin
Nakata, T., Takeda, K., Hatta, T., Kiyama, M., Moriguchi, J., Miki, S., Kawa, T., Morimoto, S., Nakamura, K., Uchida, A., et al. (1998) · Journal of Cardiovascular Pharmacology · doi:10.1097/00005344-199802000-00010 · Cited by 24
Brown, S., Chitravanshi, V. C., & Sapru, H. N. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.08.026 · Cited by 11
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
