Melanocortin 4 Receptors Reciprocally Regulate Sympathetic and Parasympathetic Preganglionic Neurons
Open accessAbstract
Melanocortin 4 receptors (MC4Rs) in the central nervous system are key regulators of energy and glucose homeostasis. Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obesity-induced hypertension. Although these effects are probably dependent upon the activity of the autonomic nervous system, the cellular effects of MC4Rs on parasympathetic and sympathetic neurons remain undefined. Here, we show that MC4R agonists inhibit parasympathetic preganglionic neurons in the brainstem. In contrast, MC4R agonists activate sympathetic preganglionic neurons in the spinal cord. Deletion of MC4Rs in cholinergic neurons resulted in elevated levels of insulin. Furthermore, re-expression of MC4Rs specifically in cholinergic neurons (including sympathetic preganglionic neurons) restores obesity-associated hypertension in MC4R null mice. These findings provide a cellular correlate of the autonomic side effects associated with MC4R agonists and demonstrate a role for MC4Rs expressed in cholinergic neurons in the regulation of insulin levels and in the development of obesity-induced hypertension.
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
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?
These hormones and receptors influence the nucleus of the solitary tract and the arcuate nucleus of the hypothalamus, which can affect set points.
“They also have influences on the nucleus of the solitary tract (NTS) as well as the arcuate nucleus of the hypothalamus, which can affect set points (da Silva et al. 2014; do Carmo et al. 2013; Sohn et al. 2013; Speakman 2014).”
From Motion sickness: more than nausea and vomiting (2014) · cites this paper as Sohn et al. 2013
The Introduction (page unavailable) says melanocortin receptors act in hypothalamic and extra-hypothalamic nuclei and links MC4R activity to energy balance. But the paper's reported brainstem effects concern the dorsal motor nucleus of the vagus, not the nucleus of the solitary tract; it does not establish effects in the arcuate nucleus or on set points. Those two nuclei appear in titles in the References, which do not establish this paper's findings. (LLM, conf=0.76)
Experimental — accuracy not yet measuredEvidence suggests that cholinergic preganglionic parasympathetic and sympathetic neuronal MC4R may contribute to elevated blood pressure in obesity.
“However, evidence suggests that cholinergic preganglionic parasympathetic and sympathetic neuronal MC4R may contribute to elevated BP in obesity208.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [208]
MC4R on cholinergic preganglionic parasympathetic and sympathetic neurons may contribute to obesity hypertension.
“The few studies that have examined chronic cardiovascular actions of MC4R in specific neuronal populations suggest a role for MC4R on cholinergic preganglionic parasympathetic and sympathetic neurons in contributing to obesity hypertension [59].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [59]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Targeted disruption of the melanocortin-4 receptor results in obesity in mice
Huszar, D., Lynch, C. A., Fairchild-Huntress, V., Dunmore, J. H., Fang, Q., Berkemeier, L. R., Gu, W., Kesterson, R. A., Boston, B. A., Cone, R. D., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)81865-6 · Cited by 3,030 · see citing works
Role of melanocortinergic neurons in feeding and the agouti obesity syndrome
Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J., & Cone, R. D. (1997) · Nature · doi:10.1038/385165a0 · Cited by 1,902 · see citing works
Clinical Spectrum of Obesity and Mutations in the Melanocortin 4 Receptor Gene
Farooqi, I. S., Keogh, J. M., Yeo, G. S. H., Lank, E. J., Cheetham, T., & O'Rahilly, S. (2003) · New England Journal of Medicine · doi:10.1056/nejmoa022050 · Cited by 1,778 · see citing works
Anatomy and regulation of the central melanocortin system
Cone, R. D. (2005) · Nature Neuroscience · doi:10.1038/nn1455 · Cited by 1,583 · see citing works
A frameshift mutation in MC4R associated with dominantly inherited human obesity
Yeo, G. S. H., Farooqi, I. S., Aminian, S., Halsall, D. J., Stanhope, R. G., & O'Rahilly, S. (1998) · Nature Genetics · doi:10.1038/2404 · Cited by 1,159 · see citing works
Mountjoy, K. G., Mortrud, M. T., Low, M. J., Simerly, R. B., & Cone, R. D. (1994) · Molecular Endocrinology · doi:10.1210/mend.8.10.7854347 · Cited by 1,157 · see citing works
Divergence of Melanocortin Pathways in the Control of Food Intake and Energy Expenditure
Balthasar, N., Dalgaard, L. T., Lee, C. E., Yu, J. H., Funahashi, H., Williams, T. B., Ferreira, M. A. R., Tang, V., McGovern, R. A., Kenny, C. D., et al. (2005) · Cell · doi:10.1016/j.cell.2005.08.035 · Cited by 1,122 · see citing works
Self-citationA frameshift mutation in human MC4R is associated with a dominant form of obesity
Vaisse, C., Clément, K., Guy-grand, B., & Froguel, P. (1998) · Nature Genetics · doi:10.1038/2407 · Cited by 1,091 · see citing works
Rossi, J., Balthasar, N., Olson, D., Scott, M., Berglund, E., Lee, C. E., Choi, M. J., Lauzon, D., Lowell, B. B., & Elmquist, J. K. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.01.010 · Cited by 672 · see citing works
Self-citationModulation 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 · see citing works
Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour
Pascoli, V., Turiault, M., & Lüscher, C. (2011) · Nature · doi:10.1038/nature10709 · Cited by 419 · see citing works
Liu, H., Kishi, T., Roseberry, A. G., Cai, X., Lee, C. E., Montez, J. M., Friedman, J. M., & Elmquist, J. K. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-18-07143.2003 · Cited by 375 · see citing works
Self-citationCentral melanocortin receptors regulate insulin action
Obici, S., Feng, Z., Tan, J., Liu, L., Karkanias, G. B., & Rossetti, L. (2001) · Journal of Clinical Investigation · doi:10.1172/jci12954 · Cited by 370 · see citing works
Central melanocortin receptors regulate insulin action
Obici, S., Feng, Z., Tan, J., Liu, L., Karkanias, G., & Rossetti, L. (2001) · Journal of Clinical Investigation · doi:10.1172/jci200112954 · Cited by 370 · see citing works
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 348 · see citing works
Self-citationThe Central Melanocortin System Can Directly Regulate Serum Insulin Levels*
Fan, W., Dinulescu, D. M., Butler, A. A., Zhou, J., Marks, D. L., & Cone, R. D. (2000) · Endocrinology · doi:10.1210/endo.141.9.7665 · Cited by 294 · see citing works
Muscle KATPChannels: Recent Insights to Energy Sensing and Myoprotection
Flagg, T. P., Enkvetchakul, D., Koster, J. C., & Nichols, C. G. (2010) · Physiological Reviews · doi:10.1152/physrev.00027.2009 · Cited by 264 · see citing works
Diógenes, M. J., Fernandes, C. D. C., Sebastião, A. M., & Ribeiro, J. A. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4454-03.2004 · Cited by 174 · see citing works
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 · see citing works
Acuna, C., & van den Pol, A. N. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1607-04.2004 · Cited by 127 · see citing works
Lin, Y., Min, M., Chiu, T., & Yang, H. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-10-04173.2003 · Cited by 116 · see citing works
Wan, S., Browning, K. N., Coleman, F. H., Sutton, G. M., Zheng, H., Butler, A. A., Berthoud, H., & Travagli, R. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.5398-07.2008 · Cited by 101 · see citing works
Quinn, K. V., Giblin, J. P., & Tinker, A. (2004) · Circulation Research · doi:10.1161/01.res.0000128513.34817.c4 · Cited by 95 · see citing works
Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones
Ni, X.-P., Butler, A. A., Cone, R. D., & Humphreys, M. H. (2006) · Journal of Hypertension · doi:10.1097/01.hjh.0000249702.49854.fa · Cited by 88 · see citing works
Glucagon-like peptide-1 excites pancreas-projecting preganglionic vagal motoneurons
Wan, S., Coleman, F. H., & Travagli, R. A. (2007) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00562.2006 · Cited by 77 · see citing works
Williams, K. W., & Smith, B. N. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.106336 · Cited by 76 · see citing works
Self-citationRapid Inhibition of Neurons in the Dorsal Motor Nucleus of the Vagus by Leptin
Williams, K. W., Zsombok, A., & Smith, B. N. (2006) · Endocrinology · doi:10.1210/en.2006-1098 · Cited by 76 · see citing works
Self-citationRole of Adrenergic Activity in Pressor Responses to Chronic Melanocortin Receptor Activation
Kuo, J. J., da Silva, A. A., Tallam, L. S., & Hall, J. E. (2004) · Hypertension · doi:10.1161/01.hyp.0000111836.54204.93 · Cited by 68 · see citing works
Smith, M. A., Hisadome, K., Al‐Qassab, H., Heffron, H., Withers, D. J., & Ashford, M. L. J. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.119479 · Cited by 60 · see citing works
Wang, L., Spary, E. J., Deuchars, J., & Deuchars, S. A. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2951-08.2008 · Cited by 42 · see citing works
Flagged first, then by citations
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 · see citing works
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 · see citing works
Asprosin is a centrally acting orexigenic hormone
Duerrschmid, C., He, Y., Wang, C., Li, C., Bournat, J. C., Romere, C., Saha, P. K., Lee, M. E., Phillips, K. J., Jain, M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4432 · Cited by 357 · see citing works
Motion sickness: more than nausea and vomiting
Lackner, J. R. (2014) · Experimental Brain Research · doi:10.1007/s00221-014-4008-8 · Cited by 314 · see citing works
“They also have influences on the nucleus of the solitary tract (NTS) as well as the arcuate nucleus of the hypothalamus, which can affect set points (da Silva et al. 2014; do Carmo et al. 2013; Sohn et al. 2013; Speakman 2014).”
BackgroundBrain regulation of energy balance and body weight
Rui, L. (2013) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-013-9261-9 · Cited by 168 · see citing works
Latest approaches for the treatment of obesity
Jackson, V. M., Breen, D. M., Fortin, J.-P., Liou, A., Kuzmiski, J. B., Loomis, A. K., Rives, M.-L., Shah, B., & Carpino, P. A. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2015.1044966 · Cited by 132 · see citing works
Neural melanocortin receptors in obesity and related metabolic disorders
Girardet, C., & Butler, A. A. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.004 · Cited by 128 · see citing works
Kimura, K., Tanida, M., Nagata, N., Inaba, Y., Watanabe, H., Nagashimada, M., Ota, T., Asahara, S.-I., Kido, Y., Matsumoto, M., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.02.032 · Cited by 84 · see citing works
The Brain Melanocortin System, Sympathetic Control, and Obesity Hypertension
da Silva, A. A., do Carmo, J. M., Wang, Z., & Hall, J. E. (2014) · Physiology · doi:10.1152/physiol.00061.2013 · Cited by 47 · see citing works
Acquired hypothalamic obesity: A clinical overview and update
Roth, C. L., & McCormack, S. E. (2024) · Diabetes, Obesity and Metabolism · doi:10.1111/dom.15530 · Cited by 42 · see citing works
Role of the brain melanocortins in blood pressure regulation
do Carmo, J. M., da Silva, A. A., Wang, Z., Fang, T., Aberdein, N., Perez de Lara, C. E., & Hall, J. E. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.03.003 · Cited by 38 · see citing works
da Silva, A. A., do Carmo, J. M., Dubinion, J. H., Bassi, M., Mokhtarpouriani, K., Hamza, S. M., & Hall, J. E. (2015) · Hypertension · doi:10.1161/hypertensionaha.114.03999 · Cited by 18 · see citing works
“For example, acute stimulation of MC4R in the paraventricular nucleus or intermediolateral medulla raises renal SNA and HR, respectively,(32,33) whereas MC4R located on cholinergic preganglionic parasympathetic and sympathetic neurons seem to contribute, at least in part, to obesity hypertension.(34) However, addition…”
BackgroundDirect modulation of TRPC ion channels by Gα proteins
Kang, H., Kim, J., Park, C. H., Jeong, B., & So, I. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1362987 · Cited by 14 · see citing works
Heaton, E. C., Seo, E. H., Butkovich, L. M., Yount, S. T., & Gourley, S. L. (2024) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2024.102629 · Cited by 8 · see citing works
- Authors
- Sohn, J.-W., Harris, L. E., Berglund, E. D., Liu, T., Vong, L., Lowell, B. B., Balthasar, N., Williams, K. W., & Elmquist, J. K.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Bristol (GB)
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Balthasar, Nina
- Williams, Kevin W.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2013-01
- Volume
- 152
- Issue
- 3
- Pages
- 612-619
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3711728
- OpenAlex
- W2162613917
- Cited by
- 218
- References
- 30
- Citations by year
- 2026: 8 · 2025: 10 · 2024: 14 · 2023: 15 · 2022: 8 · 2021: 10 · 2020: 12 · 2019: 7 · 2018: 24 · 2017: 15 · 2016: 21 · 2015: 30 · 2014: 28 · 2013: 16
- FWCI
- 17.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Bristol Research (University of Bristol) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Explore Bristol Research (submittedVersion, other-oa)
- Funders
- American Diabetes Association (07-11-MN-16)
- American Heart Association
- British Heart Foundation (FS/06/057)
- Lister Institute of Preventive Medicine
- National Institutes of Health (DK057521, DK046200)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK057521, RL1DK081185, R01DK075632, P30DK046200, R37DK053301, F32DK078478, R01DK088423, P01DK088761, F32DK092083, K01DK087780)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroscience of respiration and sleep
- Keywords
- melanocortin-4 receptor, sympathetic preganglionic neurons, parasympathetic preganglionic neurons, cholinergic neurons, MC4R agonist, obesity-related hypertension, hyperinsulinemia, insulin regulation, autonomic nervous system, brainstem, spinal cord, energy homeostasis
- MeSH terms
- Cyclic AMP, Animals, Blood Pressure, Brain Stem, Humans, Insulin, Male, Neurons, Obesity, Parasympathetic Nervous System, Spinal Cord, Sympathetic Nervous System, Receptor, Melanocortin, Type 4, Mice, KATP Channels, Electrophysiological Phenomena, Cholinergic Neurons
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
