Melanocortin Signalling and the Regulation of Blood Pressure in Human Obesity: Melanocortin signalling and blood pressure
Abstract
Obesity has reached epidemic proportions worldwide. Sympathetic nervous system activation has been shown to play a major role linking obesity to the development of associated metabolic complications, such as hypertension. Recent evidence has implicated central melanocortin signalling in the regulation of blood pressure in rodents and humans. The importance of sympathetic neural activity in mediating this association has been highlighted. Humans with loss-of-function mutations in the melanocortin 4 receptor (MC4R) are an ideal group of subjects in whom the importance of melanocortin signalling in linking obesity to hypertension can be studied. Consistent with rodent studies, it was recently demonstrated that humans with MC4R deficiency have lower blood pressure, less hypertension, lower 24-h urinary catecholamine excretion, lower resting heart rate and attenuated insulin-mediated sympathetic activation compared to equally-obese humans. In overweight and obese humans without MC4R mutations, the infusion of a highly-selective MC4R agonist led to dose-dependent increases in blood pressure and heart rate. All effects were independent of insulin. This evidence supports the notion that the melanocortin system regulates blood pressure and sympathetic neural function. The results obtained in rodent and human studies, in relation to blood pressure and sympathetic function, may limit the use of MC4R agonists for the treatment of obesity. Future studies will determine whether MC4R deficiency is associated with protection from development of the detrimental cardiovascular consequences that accompany obesity.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
Compared with control individuals with obesity and intact MC4R signalling, individuals with MC4R deficiency had a lower prevalence of hypertension and reduced noradrenaline excretion despite severe obesity, insulin resistance and dyslipidemia.
“Compared with control individuals with obesity and intact MC4R signalling, individuals with MC4R deficiency had a lower prevalence of hypertension and reduced noradrenaline excretion despite severe obesity, insulin resistance and dyslipidemia199,200.”
From Obesity, kidney dysfunction and hypertension: mechanistic links (2019) · cites this paper as [200]
Hypertension prevalence is lower in MC4R deficient humans compared to control subjects, despite severe obesity and associated metabolic disorders.
“Hypertension prevalence is lower in MC4R deficient humans compared to control subjects, despite severe obesity and associated metabolic disorders125,126.”
From Obesity-Induced Hypertension: Interaction of Neurohumoral and Renal Mechanisms (2015) · cites this paper as [125]
Subjects with melanocortin-4 receptor deficiency exhibit reductions in blood pressure compared to obese subjects with normal melanocortin-4 receptor function despite severe obesity.
“Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, urinary catecholamine excretion and SNS responses to cold stimuli compared to obese subjects with normal MC4R function.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [54]
Subjects with melanocortin-4 receptor deficiency exhibit reductions in heart rate compared to obese subjects with normal melanocortin-4 receptor function despite severe obesity.
“Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, urinary catecholamine excretion and SNS responses to cold stimuli compared to obese subjects with normal MC4R function.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [54]
Subjects with melanocortin-4 receptor deficiency exhibit reductions in sympathetic nervous system responses to cold stimuli compared to obese subjects with normal melanocortin-4 receptor function despite severe obesity.
“Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, urinary catecholamine excretion and SNS responses to cold stimuli compared to obese subjects with normal MC4R function.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [54]
Subjects with melanocortin-4 receptor deficiency exhibit reductions in urinary catecholamine excretion compared to obese subjects with normal melanocortin-4 receptor function despite severe obesity.
“Despite having severe obesity, subjects with MC4R deficiency exhibit reductions in BP, heart rate, urinary catecholamine excretion and SNS responses to cold stimuli compared to obese subjects with normal MC4R function.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [54]
Patients with MC4R deficiency exhibit lower blood pressure compared to obese subjects with normal MC4R function despite severe metabolic abnormalities.
“Patients with MC4R deficiency exhibit lower BP, reduced 24-hr norepinephrine excretion, and reduced prevalence of hypertension despite severe metabolic abnormalities, compared to obese subjects with normal MC4R function [54].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [54]
In obese humans and obese rodents functional MC4Rs may be required for normal sympathetic responses to acute stress as well as increases in sympathetic nervous system activity and blood pressure.
“These observations suggest that in obese humans and obese rodents functional MC4Rs may be required for normal sympathetic responses to acute stress as well as increases in SNS activity and BP.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [54]
Patients with MC4R deficiency exhibit reduced prevalence of hypertension compared to obese subjects with normal MC4R function despite severe metabolic abnormalities.
“Patients with MC4R deficiency exhibit lower BP, reduced 24-hr norepinephrine excretion, and reduced prevalence of hypertension despite severe metabolic abnormalities, compared to obese subjects with normal MC4R function [54].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [54]
Patients with MC4R deficiency exhibit reduced 24-hour norepinephrine excretion compared to obese subjects with normal MC4R function despite severe metabolic abnormalities.
“Patients with MC4R deficiency exhibit lower BP, reduced 24-hr norepinephrine excretion, and reduced prevalence of hypertension despite severe metabolic abnormalities, compared to obese subjects with normal MC4R function [54].”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [54]
Cites
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
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
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 · see citing works
Receptor-mediated regional sympathetic nerve activation by leptin.
Haynes, W. G., Morgan, D. A., Walsh, S. A., Mark, A. L., & Sivitz, W. I. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119532 · Cited by 979 · see citing works
Farooqi, I. S., Yeo, G. S. H., Keogh, J. M., Aminian, S., Jebb, S. A., Butler, G. E., Cheetham, T. D., & O’Rahilly, S. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9397 · Cited by 801 · see citing works
βAR Signaling Required for Diet-Induced Thermogenesis and Obesity Resistance
Bachman, E. S., Dhillon, H., Zhang, C.-Y., Cinti, S., Bianco, A. C., Kobilka, B. K., & Lowell, B. B. (2002) · Science · doi:10.1126/science.1073160 · Cited by 782 · see citing works
The Effect of Weight Loss on the Sensitivity of Blood Pressure to Sodium in Obese Adolescents
Rocchini, A. P., Key, J., Bondie, D., Chico, R., Moorehead, C., Katch, V., & Martin, M. (1989) · New England Journal of Medicine · doi:10.1056/nejm198908313210905 · Cited by 621 · see citing works
Forecasting the effects of obesity and smoking on U.S. life expectancy
Stewart, S. T., Cutler, D. M., & Rosen, A. B. (2009) · New England Journal of Medicine · doi:10.1056/nejmsa0900459 · Cited by 478 · see citing works
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 · see citing works
Self-citationFarooqi, I. S., & O’Rahilly, S. (2005) · Annual Review of Medicine · doi:10.1146/annurev.med.56.062904.144924 · Cited by 439 · see citing works
The sympathetic nervous system and the metabolic syndrome
Mancia, G., Bousquet, P., Elghozi, J. L., Esler, M., Grassi, G., Julius, S., Reid, J., & Van Zwieten, P. A. (2007) · Journal of Hypertension · doi:10.1097/hjh.0b013e328048d004 · Cited by 385 · see citing works
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 · see citing works
Overweight, Obesity, and Blood Pressure: The Effects of Modest Weight Reduction
Mertens, I. L., & Gaal, L. F. V. (2000) · Obesity Research · doi:10.1038/oby.2000.32 · Cited by 330 · see citing works
Current and Potential Drugs for Treatment of Obesity
Bray, G. A., & Greenway, F. L. (1999) · Endocrine Reviews · doi:10.1210/edrv.20.6.0383 · Cited by 326 · see citing works
Role of Selective Leptin Resistance in Diet-Induced Obesity Hypertension
Rahmouni, K., Morgan, D. A., Morgan, G. M., Mark, A. L., & Haynes, W. G. (2005) · Diabetes · doi:10.2337/diabetes.54.7.2012 · Cited by 319 · see citing works
Lee, P., Greenfield, J. R., Ho, K. K. Y., & FULHAM, M. J. (2010) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00298.2010 · Cited by 314 · see citing works
Self-citationMouse models of the metabolic syndrome
Kennedy, A. J., Ellacott, K. L. J., King, V. L., & Hasty, A. H. (2010) · Disease Models & Mechanisms · doi:10.1242/dmm.003467 · Cited by 265 · see citing works
Sympathetic system activity in obesity and metabolic syndrome
TENTOLOURIS, N., LIATIS, S., & KATSILAMBROS, N. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1367.010 · Cited by 260 · see citing works
Mark, A. L., Shaffer, R. A., Correia, M. L. G., Morgan, D. A., Sigmund, C. D., & Haynes, W. G. (1999) · Journal of Hypertension · doi:10.1097/00004872-199917121-00026 · Cited by 254 · see citing works
Regulation of leptin production: sympathetic nervous system interactions
Rayner, D. V., & Trayhurn, P. (2001) · Journal of Molecular Medicine · doi:10.1007/s001090100198 · Cited by 250 · see citing works
The vasodilator action of insulin. Implications for the insulin hypothesis of hypertension.
Anderson, E. A., & Mark, A. L. (1993) · Hypertension · doi:10.1161/01.hyp.21.2.136 · Cited by 242 · see citing works
Autonomic nervous system activity in weight gain and weight loss
Arone, L. J., Mackintosh, R. M., Rosenbaum, M. S., Leibel, R. L., & Hirsch, J. (1995) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1995.269.1.r222 · Cited by 224 · see citing works
The melanocortin receptors: Lessons from knockout models
Butler, A. A., & Cone, R. D. (2002) · Neuropeptides · doi:10.1054/npep.2002.0890 · Cited by 222 · see citing works
Sympathetic innervation of white adipose tissue and its regulation of fat cell number
Bowers, R. R., Festuccia, W. T., Song, C. K., Shi, H., Migliorini, R. H., & Bartness, T. J. (2004) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00558.2003 · Cited by 221 · see citing works
Mechanisms of Abnormal Renal Sodium Handling in Obesity Hypertension
Hall, J. (1997) · American Journal of Hypertension · doi:10.1016/s0895-7061(97)00075-7 · Cited by 213 · see citing works
Pathophysiology of obesity hypertension
Hall, J. E. (2000) · Current Hypertension Reports · doi:10.1007/s11906-000-0073-4 · Cited by 185 · see citing works
Obesity-Induced Hypertension: New Concepts From the Emerging Biology of Obesity
Mark, A. L., Correia, M., Morgan, D. A., Shaffer, R. A., & Haynes, W. G. (1999) · Hypertension · doi:10.1161/01.hyp.33.1.537 · Cited by 185 · see citing works
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 · see citing works
Hypothalamic Arcuate Nucleus Mediates the Sympathetic and Arterial Pressure Responses to Leptin
Rahmouni, K., & Morgan, D. A. (2006) · Hypertension · doi:10.1161/01.hyp.0000254827.59792.b2 · Cited by 180 · see citing works
Larsen, L. H., Echwald, S. M., Sørensen, T. I. A., Andersen, T., Wulff, B. S., & Pedersen, O. B. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0497 · Cited by 176 · see citing works
Monogenic Human Obesity Syndromes
Farooqi, I. S. (2004) · Recent Progress in Hormone Research · doi:10.1210/rp.59.1.409 · Cited by 170 · see citing works
Prior, L. J., Eikelis, N., Armitage, J. A., Davern, P. J., Burke, S. L., Montani, J.-P., Barzel, B., & Head, G. A. (2010) · Hypertension · doi:10.1161/hypertensionaha.109.141119 · Cited by 157 · see citing works
Role of the Central Melanocortin Circuitry in Adaptive Thermogenesis of Brown Adipose Tissue
Voss-Andreae, A., Murphy, J. G., Ellacott, K. L. J., Stuart, R. C., Nillni, E. A., Cone, R. D., & Fan, W. (2006) · Endocrinology · doi:10.1210/en.2006-1389 · Cited by 156 · see citing works
Bray, G. A. (2000) · International Journal of Obesity · doi:10.1038/sj.ijo.0801269 · Cited by 153 · see citing works
Autonomic and Hemodynamic Responses to Insulin in Lean and Obese Humans
Muscelli, E., Emdin, M., Natali, A., Pratali, L., Camastra, S., Gastaldelli, A., Baldi, S., Carpeggiani, C., & Ferrannini, E. (1998) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.83.6.4878 · Cited by 143 · see citing works
Melanocortin-4 Receptor Mediates Chronic Cardiovascular and Metabolic Actions of Leptin
Tallam, L. S., da Silva, A. A., & Hall, J. E. (2006) · Hypertension · doi:10.1161/01.hyp.0000227966.36744.d9 · Cited by 133 · see citing works
Sympathetic Overdrive and Cardiovascular Risk in the Metabolic Syndrome
Grassi, G. M. (2006) · Hypertension Research · doi:10.1291/hypres.29.839 · Cited by 131 · see citing works
Song, C. K., Jackson, R. M., Harris, R. B. S., Richard, D., & Bartness, T. J. (2005) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00348.2005 · Cited by 120 · see citing works
Hypothalamic Melanocortin Receptors and Chronic Regulation of Arterial Pressure and Renal Function
Kuo, J. J., Silva, A. A., & Hall, J. E. (2003) · Hypertension · doi:10.1161/01.hyp.0000048194.97428.1a · Cited by 113 · see citing works
Skibicka, K. P., & Grill, H. J. (2009) · Endocrinology · doi:10.1210/en.2009-0804 · Cited by 113 · see citing works
Current and Potential Drugs for Treatment of Obesity
Bray, G. A. (1999) · Endocrine Reviews · doi:10.1210/er.20.6.805 · Cited by 111 · see citing works
Pathogenesis of weight-related changes in blood pressure in dogs.
Rocchini, A. P., Moorehead, C., DeRemer, S. J., & Bondie, D. (1989) · Hypertension · doi:10.1161/01.hyp.13.6.922 · Cited by 110 · see citing works
Tentolouris, N., Tsigos, C., Perea, D., Koukou, E., Kyriaki, D., Kitsou, E., Daskas, S., Daifotis, Z., Makrilakis, K., Raptis, S., et al. (2003) · Metabolism · doi:10.1016/s0026-0495(03)00322-6 · Cited by 101 · see citing works
New advances in the genetics of early onset obesity
Farooqi, I. S., & O’Rahilly, S. (2005) · International Journal of Obesity · doi:10.1038/sj.ijo.0803056 · Cited by 89 · 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
Sympathetic Function in Human Carriers of Melanocortin-4 Receptor Gene Mutations
Sayk, F., Heutling, D., Dodt, C., Iwen, K. A., Wellhoner, J. P., Scherag, S., Hinney, A., Hebebrand, J., & Lehnert, H. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2297 · Cited by 86 · see citing works
The Importance of Brown Adipose Tissue
Timmons, J. A., & Pedersen, B. K. (2009) · New England Journal of Medicine · doi:10.1056/nejmc091009 · Cited by 84 · see citing works
Resistance to Metabolic Actions of Insulin and Its Role in Hypertension
Hall, J. E., Summers, R. L., Brands, M. W., Keen, H. L., & Alonso‐Galicia, M. (1994) · American Journal of Hypertension · doi:10.1093/ajh/7.8.772 · Cited by 84 · see citing works
da Silva, A. A., do Carmo, J. M., Kanyicska, B., Dubinion, J., Brandon, E., & Hall, J. E. (2008) · Hypertension · doi:10.1161/hypertensionaha.107.100636 · Cited by 79 · see citing works
Role 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
Acheson, K. J., Ravussin, É., Schoeller, D. A., Christin, L., Bourquin, L. D., Baertschi, P., Danforth, E., & Jéquier, E. (1988) · Metabolism · doi:10.1016/0026-0495(88)90035-2 · Cited by 65 · see citing works
Alharbi, K. K., Spanakis, E., Tan, K. M. L., Smith, M. J., Aldahmesh, M. A., O’Dell, S. D., Sayer, A. A., Lawlor, D. A., Ebrahim, S. B. J., Smith, G. D., et al. (2006) · Human Mutation · doi:10.1002/humu.20404 · Cited by 65 · see citing works
Defective Melanocortin 4 Receptors in Hyperphagia and Morbid Obesity
List, J. F., & Habener, J. F. (2003) · New England Journal of Medicine · doi:10.1056/nejme030013 · Cited by 64 · see citing works
Altered Cardiac Autonomic Function May Precede Insulin Resistance in Metabolic Syndrome
Chang, C., Yang, Y., Lu, F., Lin, T., Chen, J., Yeh, T. L., Wu, C., & Wu, J. (2010) · The American Journal of Medicine · doi:10.1016/j.amjmed.2009.07.031 · Cited by 62 · see citing works
The neurobiology of human obesity
Eikelis, N., & Esler, M. (2005) · Experimental Physiology · doi:10.1113/expphysiol.2005.031385 · Cited by 61 · see citing works
Greenfield, J. R., Samaras, K., Chisholm, D. J., & Campbell, L. V. (2006) · International Journal of Cardiology · doi:10.1016/j.ijcard.2005.12.007 · Cited by 56 · see citing works
Self-citationSCHEIDEGGER, K., O’Connell, M., Robbins, D. C., & Danforth, E. (1984) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-58-5-895 · Cited by 55 · see citing works
do Carmo, J. M., Hall, J. E., & da Silva, A. A. (2008) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00265.2008 · Cited by 47 · see citing works
Tsujii, S., & Bray, G. A. (1998) · Physiology & Behavior · doi:10.1016/s0031-9384(97)00518-0 · Cited by 45 · see citing works
Weight reduction for treatment of obesity-associated hypertension: Nuances and challenges
Mark, A. L. (2007) · Current Hypertension Reports · doi:10.1007/s11906-007-0068-5 · Cited by 24 · see citing works
Obesity and the Insulin Resistance Syndrome
Landsberg, L. (1996) · Hypertension Research · doi:10.1291/hypres.19.supplementi_s51 · Cited by 24 · see citing works
The importance of brown adipose tissue.
Lee, P. C., Ho, K. K. Y., & FULHAM, M. J. (2009) · PubMed · Cited by 23 · see citing works
Cardiovascular Side Effects of Antiobesity Drugs
Mark, A. L. (2009) · Circulation · doi:10.1161/circulationaha.109.888529 · Cited by 10 · see citing works
Feeding signals to the hungry mind
Balthasar, N. (2009) · Experimental Physiology · doi:10.1113/expphysiol.2008.042226 · Cited by 7 · 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
Obesity, hypertension, and chronic kidney disease
Hall, J., Juncos, L., Wang, Z., Hall, M., do Carmo, J., & da Silva, A. (2014) · International Journal of Nephrology and Renovascular Disease · doi:10.2147/ijnrd.s39739 · Cited by 520 · see citing works
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 381 · see citing works
Melanocortin-4 receptor–regulated energy homeostasis
Krashes, M. J., Lowell, B. B., & Garfield, A. S. (2016) · Nature Neuroscience · doi:10.1038/nn.4202 · Cited by 359 · see citing works
Regensteiner, J. G., Golden, S., Huebschmann, A. G., Barrett-Connor, E., Chang, A. Y., Chyun, D., Fox, C. S., Kim, C., Mehta, N., Reckelhoff, J. F., et al. (2015) · Circulation · doi:10.1161/cir.0000000000000343 · Cited by 334 · see citing works
The melanocortin pathway and control of appetite-progress and therapeutic implications
Baldini, G., & Phelan, K. D. (2019) · Journal of Endocrinology · doi:10.1530/joe-18-0596 · Cited by 279 · see citing works
Obesity, kidney dysfunction, and inflammation: interactions in hypertension
Hall, J. E., Mouton, A. J., da Silva, A. A., Omoto, A. C. M., Wang, Z., Li, X., & do Carmo, J. M. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa336 · Cited by 280 · see citing works
Limitations in anti-obesity drug development: the critical role of hunger-promoting neurons
Dietrich, M. O., & Horváth, T. L. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3739 · Cited by 202 · see citing works
Genetic approaches to understanding human obesity
Ramachandrappa, S., & Farooqi, I. S. (2011) · Journal of Clinical Investigation · doi:10.1172/jci46044 · Cited by 194 · see citing works
Christoffersen, B. Ø., Sanchez‐Delgado, G., John, L. M., Ryan, D. H., Raun, K., & Ravussin, E. (2022) · Obesity · doi:10.1002/oby.23374 · Cited by 142 · see citing works
“Several MC4R agonists failed in the clinic because of increased blood pressure or lack of efficacy combined with hyperpigmentation owing to off- target activity on MC1R (67,68).”
BackgroundLatest 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
Mechanisms underlying current and future anti-obesity drugs
Adan, R. A. H. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.12.001 · Cited by 106 · see citing works
Gq/11α and Gsα mediate distinct physiological responses to central melanocortins
Li, Y., Shrestha, Y. B., Pandey, M., Chen, M., Kablan, A., Gavrilova, O., Offermanns, S., & Weinstein, L. S. (2015) · Journal of Clinical Investigation · doi:10.1172/jci76348 · Cited by 102 · see citing works
Mechanisms and treatment of obesity-related hypertension—Part 1: Mechanisms
Parvanova, A. I., Reseghetti, E., Abbate, M., & Ruggenenti, P. L. (2023) · Clinical Kidney Journal · doi:10.1093/ckj/sfad282 · Cited by 98 · see citing works
Biased signaling at neural melanocortin receptors in regulation of energy homeostasis
Yang, L.-K., & Tao, Y. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.04.010 · Cited by 85 · see citing works
Obesity-Induced Hypertension: Brain Signaling Pathways
do Carmo, J. M., da Silva, A. A., Wang, Z., Fang, T., Aberdein, N., Rodriguez, C. E. P. D. L., & Hall, J. E. (2016) · Current Hypertension Reports · doi:10.1007/s11906-016-0658-1 · Cited by 64 · see citing works
Role of leptin and central nervous system melanocortins in obesity hypertension
da Silva, A. A., Carmo, J. M. D., & Hall, J. E. (2013) · Current Opinion in Nephrology and Hypertension · doi:10.1097/mnh.0b013e32835d0c05 · Cited by 63 · see citing works
The Role of the Melanocortin System in Metabolic Disease: New Developments and Advances
Hill, J. W., & Faulkner, L. D. (2016) · Neuroendocrinology · doi:10.1159/000450649 · Cited by 56 · see citing works
Eating behaviour in obese patients with melanocortin-4 receptor mutations: a literature review
Valette, M., Bellisle, F., Carette, C., Poitou, C., Dubern, B., Paradis, G., Herçberg, S., Muzard, L., Clément, K., & Czernichow, S. (2012) · International Journal of Obesity · doi:10.1038/ijo.2012.169 · Cited by 57 · see citing works
Singh, U., Jiang, J., Saito, K., Toth, B. A., Dickey, J. E., Rodeghiero, S. R., Deng, Y., Deng, G., Xue, B., Zhu, Z., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101401 · Cited by 56 · see citing works
Rare genetic forms of obesity: From gene to therapy
Clément, K., Mosbah, H., & Poitou, C. (2020) · Physiology & Behavior · doi:10.1016/j.physbeh.2020.113134 · Cited by 53 · see citing works
Shi, Z., & Brooks, V. L. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.284638 · Cited by 48 · see citing works
Peptides and Their Potential Role in the Treatment of Diabetes and Obesity
Greenwood, H. C., Bloom, S. R., & Murphy, K. G. (2011) · The Review of Diabetic Studies · doi:10.1900/rds.2011.8.355 · Cited by 48 · see citing works
Personalized nutrition and obesity
Qi, L. (2014) · Annals of Medicine · doi:10.3109/07853890.2014.891802 · Cited by 45 · see citing works
Boughton, C. K., & Murphy, K. G. (2012) · British Journal of Pharmacology · doi:10.1111/bph.12037 · Cited by 42 · see citing works
Melanocortin neurons: Multiple routes to regulation of metabolism
Shen, W.-J., Yao, T. S., Kong, X., Williams, K. W., & Liu, T. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.05.007 · Cited by 41 · see citing works
Melanocortin-4 Receptors and Sympathetic Nervous System Activation in Hypertension
da Silva, A. A., do Carmo, J. M., Wang, Z., & Hall, J. E. (2019) · Current Hypertension Reports · doi:10.1007/s11906-019-0951-x · Cited by 40 · see citing works
Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity
Samuelsson, A., Mullier, A., Maicas, N., Oosterhuis, N. R., Bae, S., Novoselova, T. V., Chan, L. F., Pombo, J., Taylor, P. D., Joles, J. A., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1607464113 · Cited by 39 · 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
Control of metabolic and cardiovascular function by the leptin–brain melanocortin pathway
do Carmo, J. M., da Silva, A. A., Dubinion, J., Sessums, P. O., Ebaady, S. H., Wang, Z., & Hall, J. E. (2013) · IUBMB Life · doi:10.1002/iub.1187 · Cited by 36 · see citing works
A Life without Hunger: The Ups (and Downs) to Modulating Melanocortin-3 Receptor Signaling
Butler, A. A., Clemence, G., Mavrikaki, M., Trevaskis, J. L., Macarthur, H., Marks, D. L., & Farr, S. A. (2017) · Frontiers in Neuroscience · doi:10.3389/fnins.2017.00128 · Cited by 35 · see citing works
Facilitation of breathing by leptin effects in the central nervous system
Bassi, M., Furuya, W. I., Zoccal, D. B., Menani, J. V., Colombari, D. S. A., Mulkey, D. K., & Colombari, E. (2015) · The Journal of Physiology · doi:10.1113/jp270308 · Cited by 33 · see citing works
Control of respiratory and cardiovascular functions by leptin
Bassi, M., Furuya, W. I., Zoccal, D. B., Menani, J. V., Colombari, E., Hall, J. E., da Silva, A. A., do Carmo, J. M., & Colombari, D. S. A. (2015) · Life Sciences · doi:10.1016/j.lfs.2015.01.019 · Cited by 33 · see citing works
Hall, M. E., & Hall, J. E. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-42973-3.00005-6 · Cited by 33 · see citing works
Melanocortin Pathways: Suppressed and Stimulated Melanocortin-4 Receptor (MC4R)
Hainer, V., Hainerová, I. A., Kunešová, M., Braunerová, R. T., Zamrazilová, H., & Bendlová, B. (2020) · Physiological Research · doi:10.33549/physiolres.934512 · Cited by 27 · see citing works
Spradley, F. T., Palei, A. C., & Granger, J. P. (2013) · Physiological Reports · doi:10.1002/phy2.81 · Cited by 25 · see citing works
Pan, X.-C., Song, Y.-T., Liu, C., Xiang, H., & Lu, C. (2013) · Journal of Huazhong University of Science and Technology [Medical Sciences] · doi:10.1007/s11596-013-1096-9 · Cited by 23 · see citing works
Roth, J. D., D’Souza, L. J., Griffin, P. S., Athanacio, J., Trevaskis, J. L., Nazarbaghi, R., Jodka, C. M., Athanacio, J., Hoyt, J., Forood, B., et al. (2012) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2012.01570.x · Cited by 22 · see citing works
Genetic testing in patients with obesity
Phan-Hug, F., Beckmann, J. S., & Jacquemont, S. (2012) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2011.11.010 · Cited by 21 · see citing works
da Silva, A. A., Spradley, F. T., Granger, J. P., Hall, J. E., & do Carmo, J. M. (2015) · Journal of Neurophysiology · doi:10.1152/jn.00911.2014 · Cited by 21 · see citing works
Gao, L., Wang, L., Yang, H., Pan, H., Gong, F., & Zhu, H. (2019) · International Journal of Endocrinology · doi:10.1155/2019/4328909 · Cited by 20 · see citing works
MC4R in Central and Peripheral Systems
Wei, R., Li, D., Jia, S., Chen, Y., & Wang, J. (2023) · Advanced Biology · doi:10.1002/adbi.202300035 · Cited by 18 · see citing works
Vascular effects of deletion of melanocortin-4 receptors in rats
Stepp, D. W., Osakwe, C. C., de Chantemèle, E. J. B., & MINTZ, J. D. (2013) · Physiological Reports · doi:10.1002/phy2.146 · Cited by 18 · see citing works
Balapattabi, K., Yavuz, Y., Jiang, J., Deng, G., Mathieu, N. M., Ritter, M. L., Opichka, M. A., Reho, J. J., McCorvy, J. D., Nakagawa, P., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112935 · Cited by 14 · see citing works
Dittmann, M. T., Lakatos, G., Wainwright, J. F., Mokrosiński, J., Cross, E., Farooqi, I. S., Wallis, N. J., Halsey, L. G., Wilson, R. P., O’Rahilly, S., et al. (2024) · Science Advances · doi:10.1126/sciadv.adj3823 · Cited by 15 · see citing works
Role of melanocortin 4 receptor in hypertension induced by chronic intermittent hypoxia
do Carmo, J. M., da Silva, A. A., Moak, S. P., da Silva, F. S., Spradley, F. T., & Hall, J. E. (2018) · Acta Physiologica · doi:10.1111/apha.13222 · Cited by 14 · see citing works
Pedroso, J. A. B., da Silva, I. B., Zampieri, T. T., Totola, L. T., Moreira, T. S., Taniguti, A. P. T., Diniz, G. P., Barreto‐Chaves, M. L. M., & Donato, J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23126484 · Cited by 13 · see citing works
Mechanisms Underlying Hypertension and Obesity
Carlson, S. H., & Wyss, J. M. (2011) · Hypertension · doi:10.1161/hypertensionaha.110.161729 · Cited by 12 · see citing works
Oliveira, V., Riedl, R. A., Claflin, K. E., Mathieu, N. M., Ritter, M. L., Balapattabi, K., Wackman, K. K., Reho, J. J., Brozoski, D., Morgan, D. A., et al. (2022) · Physiological Genomics · doi:10.1152/physiolgenomics.00015.2022 · Cited by 10 · see citing works
Role of the Melanocortin System in the Central Regulation of Cardiovascular Functions
Copperi, F., Kim, J. D., & Diano, S. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.725709 · Cited by 9 · see citing works
Obesity and Metabolic Syndrome Hypertension
Hall, M. E., Wang, Z., do Carmo, J. M., Kamimura, D., & Hall, J. E. (2018) · Updates in hypertension and cardiovascular protection · doi:10.1007/978-3-319-59918-2_42 · Cited by 8 · see citing works
do Carmo, J. M., Dai, X., Aitken, N. M., Larson, K., Omoto, A. C. M., Gulke, R. R., Wang, Z., Li, X., Mouton, A. J., Hall, J. E., et al. (2023) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00106.2023 · Cited by 6 · see citing works
Blackstone, R. P. (2016) · Springer eBooks · doi:10.1007/978-3-319-39409-1_5 · Cited by 5 · see citing works
do Carmo, J. M., da Silva, A. A., & Hall, J. E. (2015) · Journal of Hypertension · doi:10.1097/hjh.0000000000000530 · Cited by 5 · see citing works
do Carmo, J. M., da Silva, A. A., Moak, S. P., Houghton, H. J., Smith, A. D., & Hall, J. E. (2015) · American Journal of Hypertension · doi:10.1093/ajh/hpv182 · Cited by 4 · see citing works
Yue, C.-J., Li, F., & Huang, Q. (2014) · Europe PMC (PubMed Central) · Cited by 4 · see citing works
Sanders, T. A. B. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-818460-8.00021-6 · Cited by 2 · see citing works
Siddiqui, I., Khan, N. A., & Haider, Z. (2025) · medRxiv · doi:10.1101/2025.10.04.25337310 · Cited by 2 · see citing works
Duquesnoy, M., Mosbah, H., Clément, K., Dubern, B., & Poitou, C. (2020) · Médecine des Maladies Métaboliques · doi:10.1016/j.mmm.2020.07.002 · Cited by 1 · see citing works
Early-Onset Obesity Caused by Monogenic Disorders
PAGE, L. C., Shi, M., & Freemark, M. (2017) · Current Pediatrics Reports · doi:10.1007/s40124-017-0132-9 · Cited by 1 · see citing works
Leptin, the Autonomic Nervous System, and Hypertension
da Silva, A. A., do Carmo, J. M., Wang, Z., & Hall, J. E. (2014) · Springer eBooks · doi:10.1007/978-3-319-09915-6_14 · Cited by 1 · see citing works
The Magel2-null mouse as a model of Prader-Willi Syndrome
Mercer, R. E. (2012) · ERA: Education and Research Archive (University of Alberta) · doi:10.7939/r3cm3m
Pathophysiology of Obesity and Cancer: Drugs and Signaling Targets
Khalid, A., Khalid, H., Faiza, N., Khalil, A. A., Shahbaz, K., Aslam, A., Shahid, Q. A., Abdulrahman, S. A., Egbuna, C., & Patrick-Iwuanyanwu, K. C. (2021) · Springer eBooks · doi:10.1007/978-3-030-72999-8_3
Sanders, T. A. B. (2012) · doi:10.1002/9781119946045.ch46
Disease Models in Safety Pharmacology
Wallis, R. M. (2022) · Springer eBooks · doi:10.1007/978-3-030-73317-9_88-1
Disease Models in Safety Pharmacology
Wallis, R. M. (2024) · Springer eBooks · doi:10.1007/978-3-031-35529-5_88
Cardiometabolic regulation by adipocyte-derived leptin and the brain melanocortin system
Hall, J. E., Omoto, A. C. M., do Carmo, J. M., da Silva, A. A., Mouton, A. J., Wang, Z., & Hall, M. E. (2026) · Clinical Science · doi:10.1042/cs20250039
Hamidi, A. K., Foroutan, M., Klashami, Z. N., Taheri, F., Asadi, M., Bandarian, F., & Amoli, M. M. (2026) · Journal of Diabetes & Metabolic Disorders · doi:10.1007/s40200-026-02050-y
Cao, D., & Zhao, Z. (2026) · IntechOpen eBooks · doi:10.5772/intechopen.1018078
- Authors
- Greenfield, J. R.
- Affiliations
- Garvan Institute of Medical Research (AU)
- Corresponding author
- Greenfield, J. R.
- ORCID
- Greenfield, J. R.
- Venue
- Journal of Neuroendocrinology
- Publisher
- Wiley
- Published
- 2011-01-10
- Volume
- 23
- Issue
- 2
- Pages
- 186-193
- ISSN
- 0953-8194 (ISSN-L)
- OpenAlex
- W2040428630
- Cited by
- 72
- References
- 64
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 5 · 2022: 4 · 2021: 3 · 2020: 6 · 2019: 4 · 2018: 2 · 2017: 6 · 2016: 5 · 2015: 9 · 2014: 5 · 2013: 7 · 2012: 7
- FWCI
- 0.55
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroendocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Diabetes Australia Research Trust
- GlaxoSmithKline Australia
- National Health and Medical Research Council
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Keywords
- melanocortin-4 receptor, obesity, hypertension, blood pressure regulation, sympathetic nervous system, MC4R agonist, catecholamine excretion, heart rate, cardiovascular risk
- MeSH terms
- Animals, Blood Pressure, Heart Rate, Humans, Hypertension, Mutation, Obesity, Sympathetic Nervous System, Signal Transduction, Receptor, Melanocortin, Type 4, Melanocortins
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
