RM-493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy expenditure in obese individuals
Open accessAbstract
CONTEXT: Activation of the melanocortin-4 receptor (MC4R) with the synthetic agonist RM-493 decreases body weight and increases energy expenditure (EE) in nonhuman primates. The effects of MC4R agonists on EE in humans have not been examined to date. OBJECTIVE, DESIGN, AND SETTING: In a randomized, double-blind, placebo-controlled, crossover study, we examined the effects of the MC4R agonist RM-493 on resting energy expenditure (REE) in obese subjects in an inpatient setting. STUDY PARTICIPANTS AND METHODS: Twelve healthy adults (6 men and 6 women) with body mass index of 35.7 ± 2.9 kg/m(2) (mean ± SD) received RM-493 (1 mg/24 h) or placebo by continuous subcutaneous infusion over 72 hours, followed immediately by crossover to the alternate treatment. All subjects received a weight-maintenance diet (50% carbohydrate, 30% fat, and 20% protein) and performed 30 minutes of standardized exercise daily. Continuous EE was measured on the third treatment day in a room calorimeter, and REE in the fasting state was defined as the mean of 2 30-minute resting periods. RESULTS: RM-493 increased REE vs placebo by 6.4% (95% confidence interval, 0.68-13.02%), on average by 111 kcal/24 h (95% confidence interval, 15-207 kcal, P = .03). Total daily EE trended higher, whereas the thermic effect of a test meal and exercise EE did not differ significantly. The 23-hour nonexercise respiratory quotient was lower during RM-493 treatment (0.833 ± 0.021 vs 0.848 ± 0.022, P = .02). No adverse effect on heart rate or blood pressure was observed. CONCLUSIONS: Short-term administration of the MC4R agonist RM-493 increases REE and shifts substrate oxidation to fat in obese individuals.
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?
Setmelanotide administration for 3 days to 12 obese adults did not raise blood pressure.
“In another study [80], setmelanotide administration for 3 days to 12 in obese adults caused significant increases in resting energy expenditure and preferential increases in fat oxidation without raising BP.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [80]
Setmelanotide administration for 3 days to 12 obese adults caused significant increases in resting energy expenditure.
“In another study [80], setmelanotide administration for 3 days to 12 in obese adults caused significant increases in resting energy expenditure and preferential increases in fat oxidation without raising BP.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [80]
Setmelanotide administration for 3 days to 12 obese adults caused preferential increases in fat oxidation.
“In another study [80], setmelanotide administration for 3 days to 12 in obese adults caused significant increases in resting energy expenditure and preferential increases in fat oxidation without raising BP.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [80]
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
1 retracted
Safarinejad, M. R. (2008) · The Journal of Sexual Medicine · doi:10.1111/j.1743-6109.2007.00698.x · Cited by 69 · see citing works
RetractedRole 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
Determinants of 24-hour energy expenditure in man. Methods and results using a respiratory chamber.
Ravussin, E., Lillioja, S., Anderson, T. E., Christin, L., & Bogardus, C. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112749 · Cited by 1,166 · see citing works
Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity
Vaisse, C., Clement, K., Durand, E., Hercberg, S., Guy-Grand, B., & Froguel, P. (2000) · Journal of Clinical Investigation · doi:10.1172/jci9238 · Cited by 897 · see citing works
Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ
ZURLO, F., Lillioja, S., Puente, A. E.-D., Nyomba, B. L. G., Raz, I., Saad, M. F., Swinburn, B. A., Knowler, W. C., Bogardus, C., & Ravussin, É. (1990) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.1990.259.5.e650 · Cited by 704 · see citing works
Integration of NPY, AGRP, and Melanocortin Signals in the Hypothalamic Paraventricular Nucleus
Cowley, M. A., Pronchuk, N., Fan, W., Dinulescu, D. M., Colmers, W. F., & Cone, R. D. (1999) · Neuron · doi:10.1016/s0896-6273(00)80829-6 · Cited by 616 · see citing works
Studies on the Physiological Functions of the Melanocortin System
Cone, R. D. (2006) · Endocrine Reviews · doi:10.1210/er.2006-0034 · Cited by 615 · see citing works
The Melanocortin-4 Receptor: Physiology, Pharmacology, and Pathophysiology
Tao, Y.-X. (2010) · Endocrine Reviews · doi:10.1210/er.2009-0037 · Cited by 531 · 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
The Central Melanocortin System and Energy Homeostasis
Cone, R. D. (1999) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(99)00153-8 · Cited by 351 · see citing works
Harris, M., Aschkenasi, C., Elias, C. F., Chandrankunnel, A., Nillni, E. A., Bjørbæk, C., Elmquist, J. K., Flier, J. S., & Hollenberg, A. N. (2001) · Journal of Clinical Investigation · doi:10.1172/jci10741 · Cited by 341 · see citing works
Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat
Butler, A. A., Marks, D. L., Fan, W., Kuhn, C. M., Bartolome, M. B., & Cone, R. D. (2001) · Nature Neuroscience · doi:10.1038/88423 · Cited by 332 · see citing works
Astrup, A., Toubro, S., Cannon, S., Hein, P., Breum, L., & Madsen, J. (1990) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/51.5.759 · Cited by 309 · see citing works
The 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
Kievit, P., Halem, H., Marks, D. L., Dong, J. Z., Glavas, M. M., Sinnayah, P., Pranger, L., Cowley, M. A., Grove, K. L., & Culler, M. D. (2013) · Diabetes · doi:10.2337/db12-0598 · Cited by 231 · see citing works
Assessing Validity and Reliability of Resting Metabolic Rate in Six Gas Analysis Systems
Cooper, J. A., Watras, A. C., O’Brien, M. J., Luke, A. H., Dobratz, J. R., Earthman, C. P., & Schoeller, D. A. (2008) · Journal of the American Dietetic Association · doi:10.1016/j.jada.2008.10.004 · Cited by 219 · see citing works
Thermogenic effects of sibutramine in humans
Hansen, D. L., Toubro, S., Stock, M. J., Macdonald, I. A., & Astrup, A. V. (1998) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/68.6.1180 · Cited by 182 · see citing works
Panaro, B. L., Tough, I. R., Engelstoft, M. S., Matthews, R. T., Digby, G. J., Møller, C. L., Svendsen, B., Gribble, F., Reimann, F., Holst, J. J., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.004 · Cited by 179 · see citing works
Melanocortin-4 Receptor in Energy Homeostasis and Obesity Pathogenesis
Hinney, A., Volckmar, A., & Knoll, N. (2013) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-386933-3.00005-4 · Cited by 160 · see citing works
Diamond, L. E., Earle, D. C., Rosen, R., Willett, M. S., & Molinoff, P. B. (2004) · International Journal of Impotence Research · doi:10.1038/sj.ijir.3901139 · Cited by 127 · see citing works
Fani, L., Bak, S., Delhanty, P., van Rossum, E. F. C., & van den Akker, E. L. T. (2014) · International Journal of Obesity · doi:10.1038/ijo.2013.80 · Cited by 121 · see citing works
Central melanocortin system modulates energy intake and expenditure of obese and lean Zucker rats
Hwa, J. J., Ghibaudi, L., Gao, J., & Parker, E. M. (2001) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.2001.281.2.r444 · Cited by 96 · see citing works
Repeatability of 24-h energy expenditure measurements in humans by indirect calorimetry
Rumpler, W. V., Seale, J., Conway, J., & Moe, P. (1990) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/51.2.147 · Cited by 92 · see citing works
Krakoff, J. A., Ma, L., Kobes, S., Knowler, W. C., Hanson, R. L., Bogardus, C., & Baier, L. J. (2008) · Diabetes · doi:10.2337/db08-0577 · Cited by 66 · see citing works
Tanaka, T., Masuzaki, H., Yasue, S., Ebihara, K., Shiuchi, T., Ishii, T., Arai, N., Hirata, M., Yamamoto, H., Hayashi, T., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.04.004 · Cited by 62 · see citing works
Heijboer, A. C., van den Hoek, A. M., Pijl, H., Voshol, P. J., Havekes, L. M., Romijn, J. A., & Corssmit, E. P. M. (2005) · Diabetologia · doi:10.1007/s00125-005-1838-8 · Cited by 43 · see citing works
Royalty, J. E., Konradsen, G., Eskerod, O., Wulff, B. S., & Hansen, B. S. (2013) · The Journal of Clinical Pharmacology · doi:10.1002/jcph.211 · Cited by 40 · see citing works
Hsiung, H. M., Hertel, J. L., Zhang, X.-Y., Smith, D. P., Smiley, D. L., Heiman, M. L., Yang, D. D., Husain, S., Mayer, J. P., Zhang, L., et al. (2005) · Endocrinology · doi:10.1210/en.2005-0177 · Cited by 26 · see citing works
Resting Energy Expenditure, Thermic Effect of Food, and Total Energy Expenditure
́quier, Y. S. A. E. J. (2003) · CRC Press eBooks · doi:10.3109/9780203913376-27 · Cited by 20 · see citing works
Flagged first, then by citations
1 of the 30 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Hypothalamic circuits regulating appetite and energy homeostasis: pathways to obesity
Timper, K., & Brüning, J. C. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.026609 · Cited by 802 · see citing works
Clément, K., van den Akker, E., Argente, J., Bahm, A., Chung, W. K., Connors, H., De Waele, K., Farooqi, I. S., Gonneau-Lejeune, J., Gordon, G., et al. (2020) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(20)30364-8 · Cited by 492 · see citing works
Proopiomelanocortin Deficiency Treated with a Melanocortin-4 Receptor Agonist
Kühnen, P., Clément, K., Wiegand, S., Blankenstein, O., Gottesdiener, K., Martini, L. L., Mai, K., Blume-Peytavi, U., Grüters, A., & Krude, H. (2016) · New England Journal of Medicine · doi:10.1056/nejmoa1512693 · Cited by 485 · 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
Cyclic peptide drugs approved in the last two decades (2001–2021)
Zhang, H., & Chen, S. (2021) · RSC Chemical Biology · doi:10.1039/d1cb00154j · Cited by 327 · see citing works
Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency
Collet, T.-H., Dubern, B., Mokrosinski, J., Connors, H., Keogh, J. M., Mendes de Oliveira, E., Henning, E., Poitou-Bernert, C., Oppert, J.-M., Tounian, P., et al. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.06.015 · Cited by 302 · see citing works
Gut-Brain Cross-Talk in Metabolic Control
Clemmensen, C., Müller, T. D., Woods, S. C., Berthoud, H., Seeley, R. J., & Tschöp, M. H. (2017) · Cell · doi:10.1016/j.cell.2017.01.025 · Cited by 296 · see citing works
Human gain-of-function MC4R variants show signaling bias and protect against obesity
Lotta, L. A., Mokrosiński, J., Mendes de Oliveira, E., Li, C., Sharp, S. J., Luan, J., Brouwers, B., Ayinampudi, V., Bowker, N., Kerrison, N., et al. (2019) · Cell · doi:10.1016/j.cell.2019.03.044 · Cited by 284 · see citing works
Advances in therapeutic peptides targeting G protein-coupled receptors
Davenport, A. P., Scully, C. C. G., de Graaf, C., Brown, A., & Maguire, J. J. (2020) · Nature Reviews Drug Discovery · doi:10.1038/s41573-020-0062-z · Cited by 276 · 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
Pharmacotherapy of obesity: available medications and drugs under investigation.
Pilitsi, E., Farr, O. M., Polyzos, S. A., Perakakis, N., Nolen-Doerr, E., Papathanasiou, A.-E., & Mantzoros, C. S. (2019) · Metabolism · doi:10.1016/j.metabol.2018.10.010 · Cited by 248 · see citing works
The melanocortin pathway and energy homeostasis: From discovery to obesity therapy
Yeo, G. S. H., Chao, D. H. M., Siegert, A., Koerperich, Z. M., Ericson, M. D., Simonds, S. E., Larson, C. M., Luquet, S. H., Clarke, I. J., Sharma, S. D., et al. (2021) · Molecular Metabolism · doi:10.1016/j.molmet.2021.101206 · Cited by 246 · see citing works
Future Pharmacotherapy for Obesity: New Anti-obesity Drugs on the Horizon
Srivastava, G., & Apovian, C. (2018) · Current Obesity Reports · doi:10.1007/s13679-018-0300-4 · Cited by 232 · see citing works
Convertible visceral fat as a therapeutic target to curb obesity
Giordano, A., Frontini, A., & Cinti, S. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.31 · Cited by 232 · see citing works
Genetic and Epigenetic Causes of Obesity
Thaker, V. (2017) · American Academy of Pediatrics eBooks · doi:10.1542/9781581109405-genetic · Cited by 221 · see citing works
Markham, A. (2021) · Drugs · doi:10.1007/s40265-021-01470-9 · Cited by 193 · see citing works
Melanocortin-4 Receptor Signalling: Importance for Weight Regulation and Obesity Treatment
Kühnen, P., Krude, H., & Biebermann, H. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.12.002 · Cited by 190 · see citing works
Obesity: Current and potential pharmacotherapeutics and targets
Narayanaswami, V., & Dwoskin, L. P. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.10.015 · Cited by 184 · see citing works
60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH
Anderson, E. J. P., Çakır, I., Carrington, S. J. S., Cone, R. D., Ghamari‐Langroudi, M., Gillyard, T. R., Gimenez, L. E., & Litt, M. J. (2016) · Journal of Molecular Endocrinology · doi:10.1530/jme-16-0014 · Cited by 149 · 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
“Although the primary factor driving weight loss was decreased appetite, an acute increase in resting energy expenditure (~6%, relative to placebo) was also observed in the clinic (70).”
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
Novel Noninvasive Approaches to the Treatment of Obesity: From Pharmacotherapy to Gene Therapy
Angelidi, A. M., Belanger, M. J., Kokkinos, A. D., Koliaki, C. C., & Mantzoros, C. S. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnab034 · Cited by 133 · see citing works
Yu, J., Gimenez, L. E., Hernández, C. C., Wu, Y., Wein, A. H., Han, G. W., McClary, K. M., Mittal, S. R., Burdsall, K. A., Stauch, B., et al. (2020) · Science · doi:10.1126/science.aaz8995 · Cited by 127 · see citing works
Appetite Regulation: Hormones, Peptides, and Neurotransmitters and Their Role in Obesity
Miller, G. D. (2017) · American Journal of Lifestyle Medicine · doi:10.1177/1559827617716376 · Cited by 126 · see citing works
A multidisciplinary approach to the clinical management of Prader–Willi syndrome
Duis, J. B., van Wattum, P. J., Scheimann, A. O., Salehi, P., Brokamp, E., Fairbrother, L., Childers, A., Shelton, A. R., Bingham, N. C., Shoemaker, A. H., et al. (2019) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.514 · Cited by 110 · see citing works
Structures of active melanocortin-4 receptor–Gs-protein complexes with NDP-α-MSH and setmelanotide
Heyder, N., Kleinau, G., Speck, D., Schmidt, A., Paisdzior, S., Szczepek, M., Bauer, B., Koch, A., Gallandi, M., Kwiatkowski, D., et al. (2021) · Cell Research · doi:10.1038/s41422-021-00569-8 · Cited by 106 · see citing works
Pediatric obesity: Current concepts
Greydanus, D. E., Agana, M. G., Kamboj, M. K., Shebrain, S., Soares, N. S., Eke, R., & Patel, D. R. (2018) · Disease-a-Month · doi:10.1016/j.disamonth.2017.12.001 · Cited by 98 · see citing works
Adipose tissue, systematic inflammation, and neurodegenerative diseases
Migliolo, L., Boleti, A. P. D. A., Cardoso, P. H. D. O., Frihling, B. E. F., Silva, P. S. E., & de Moraes, L. F. R. N. (2022) · Neural Regeneration Research · doi:10.4103/1673-5374.343891 · Cited by 90 · see citing works
Ayers, K., Glicksberg, B. S., Garfield, A., Longerich, S., White, J., Yang, P., Du, L., Chittenden, T., Gulcher, J., Roy, S., et al. (2018) · Journal of Clinical Endocrinology and Metabolism · doi:10.1210/jc.2018-00258 · Cited by 82 · see citing works
Bench-top to clinical therapies: A review of melanocortin ligands from 1954 to 2016
Ericson, M. D., Lensing, C. J., Fleming, K. A., Schlasner, K. N., Doering, S. R., & Haskell‐Luevano, C. (2017) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2017.03.020 · Cited by 86 · 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
Finan, B., Clemmensen, C., & Müller, T. D. (2015) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2015.07.003 · Cited by 81 · see citing works
da Fonseca, A. C. P., Mastronardi, C. A., Johar, A., Arcos‐Burgos, M., & Paz-Filho, G. (2017) · Journal of Diabetes and its Complications · doi:10.1016/j.jdiacomp.2017.04.026 · Cited by 82 · see citing works
Use and importance of nonhuman Primates in metabolic disease research: current state of the field
Havel, P. J., Kievit, P., Comuzzie, A. G., & Bremer, A. A. (2017) · ILAR Journal · doi:10.1093/ilar/ilx031 · Cited by 75 · see citing works
Ueno, H., & Nakazato, M. (2016) · Journal of Diabetes Investigation · doi:10.1111/jdi.12492 · Cited by 71 · see citing works
Neuronal systems and circuits involved in the control of food intake and adaptive thermogenesis
Caron, A., & Richard, D. (2016) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13263 · Cited by 68 · see citing works
Neuronal Control of Brown Fat Activity
Kooijman, S., van den Heuvel, J. K., & Rensen, P. C. N. (2015) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2015.09.008 · Cited by 64 · see citing works
Genetics and epigenetics in the obesity phenotyping scenario
Trang, B. K., & Grant, S. F. A. (2023) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-023-09804-6 · Cited by 66 · see citing works
Severe Obesity in Children and Adolescents: Metabolic Effects, Assessment, and Treatment
Chung, L. Y., & Rhie, Y. (2021) · Journal of Obesity & Metabolic Syndrome · doi:10.7570/jomes21063 · Cited by 62 · see citing works
Yamada, Y., Hashii, Y., Yokoyama, K., Itoi, A., Adachi, T., & Kimura, M. (2018) · European Journal of Applied Physiology · doi:10.1007/s00421-018-3944-6 · Cited by 58 · see citing works
Pathophysiology of melanocortin receptors and their accessory proteins
Novoselova, T. V., Chan, L. F., & Clark, A. (2018) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2018.02.002 · Cited by 57 · 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
The current state of GPCR ‐based drug discovery to treat metabolic disease
Sloop, K. W., Emmerson, P. J., Statnick, M. A., & Willard, F. S. (2018) · British Journal of Pharmacology · doi:10.1111/bph.14157 · Cited by 51 · see citing works
Prader-Willi syndrome: endocrine manifestations and management
Alves, C., & Franco, R. R. (2020) · Archives of Endocrinology and Metabolism · doi:10.20945/2359-3997000000248 · Cited by 48 · see citing works
Genetics of Obesity in East Asians
Sun, C., Kovacs, P. L., & Guiu‐Jurado, E. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2020.575049 · Cited by 45 · see citing works
MECHANISMS IN ENDOCRINOLOGY: Update on treatments for patients with genetic obesity
Poitou, C., Mosbah, H., & Clément, K. (2020) · European Journal of Endocrinology · doi:10.1530/eje-20-0363 · Cited by 43 · see citing works
Quantification of the Capacity for Cold-Induced Thermogenesis in Young Men With and Without Obesity
Brychta, R. J., Huang, S., Wang, J., Leitner, B. P., Hattenbach, J. D., Bell, S. L., Fletcher, L. A., Wood, R. P., Idelson, C. R., Duckworth, C. J., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2019-00728 · Cited by 42 · see citing works
The central melanocortin system and human obesity
Yang, Y., & Xu, Y. (2020) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjaa048 · Cited by 42 · see citing works
Setmelanotide: a promising advancement for pediatric patients with rare forms of genetic obesity
Trapp, C. M., & Censani, M. (2023) · Current Opinion in Endocrinology, Diabetes & Obesity · doi:10.1097/med.0000000000000798 · Cited by 41 · see citing works
“Unlike earlier generation MC4R agonists, individuals taking Setmelanotide have not exhibited concerning elevations in heart rate or blood pressure that led to the termination of firstgeneration MC4R agonist development [14,15].”
BackgroundGorman, S., Lucas, R. M., Aidan, A.-H., Fleury, N., & Feelisch, M. (2016) · Photochemical & Photobiological Sciences · doi:10.1039/c6pp00274a · 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
Neuronal cAMP/PKA Signaling and Energy Homeostasis
Yang, L. (2018) · Advances in experimental medicine and biology · doi:10.1007/978-981-13-1286-1_3 · Cited by 39 · see citing works
Neuronal control of peripheral nutrient partitioning
Manceau, R., Majeur, D., & Alquier, T. (2020) · Diabetologia · doi:10.1007/s00125-020-05104-9 · Cited by 40 · see citing works
Prader-Willi syndrome: reflections on seminal studies and future therapies
Chung, M. S., Langouët, M., Chamberlain, S. J., & Carmichael, G. (2020) · Open Biology · doi:10.1098/rsob.200195 · 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
A cellular and molecular basis of leptin resistance
Tan, B., Hedbacker, K., Kelly, L., Zhang, Z., Moura‐Assis, A., Luo, J., Rabinowitz, J. D., & Friedman, J. M. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.01.001 · Cited by 42 · see citing works
Neuropeptides in Obesity and Metabolic Disease
van der Klaauw, A. A. (2017) · Clinical Chemistry · doi:10.1373/clinchem.2017.281568 · Cited by 37 · see citing works
Ju, S. H., Cho, G., & Sohn, J. (2018) · Pharmacological Research · doi:10.1016/j.phrs.2018.01.004 · Cited by 37 · see citing works
Durek, T., Cromm, P. M., White, A. M., Schroeder, C. I., Kaas, Q., Weidmann, J., Fuaad, A. A. H. A., Cheneval, O., Harvey, P. J., Daly, N. L., et al. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00170 · Cited by 36 · see citing works
Severe Obesity in the Pediatric Population: Current Concepts in Clinical Care
Fox, C. K., Gross, A. C., Bomberg, E. M., Ryder, J. R., Bensignor, M. O., Bramante, C. T., & Kelly, A. S. (2019) · Current Obesity Reports · doi:10.1007/s13679-019-00347-z · Cited by 36 · see citing works
Heyder, N., Kleinau, G., Szczepek, M., Kwiatkowski, D., Speck, D., Soletto, L., Cerdá‐Reverter, J. M., Krude, H., Kühnen, P., Biebermann, H., et al. (2019) · Frontiers in Endocrinology · doi:10.3389/fendo.2019.00515 · Cited by 36 · see citing works
Magel2‐null mice are hyper‐responsive to setmelanotide, a melanocortin 4 receptor agonist
Bischof, J. M., der Ploeg, L. H. T. V., Colmers, W. F., & Wevrick, R. (2016) · British Journal of Pharmacology · doi:10.1111/bph.13540 · Cited by 36 · see citing works
Liu, T., Ji, R.-L., & Tao, Y.-X. (2022) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2021.108044 · Cited by 34 · see citing works
Targeting Energy Expenditure—Drugs for Obesity Treatment
Jimenez-Muñoz, C. M., López, M., Alberício, F., & Makowski, K. (2021) · Pharmaceuticals · doi:10.3390/ph14050435 · Cited by 35 · see citing works
Li, L., Yoo, E.-S., Li, X., Wyler, S. C., Chen, X., Wan, R., Arnold, A. G., Birnbaum, S. G., Jia, L., Sohn, J., et al. (2021) · The Journal of Experimental Medicine · doi:10.1084/jem.20202484 · Cited by 35 · 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
Anderson, E. J. P., Ghamari‐Langroudi, M., Çakır, I., Litt, M. J., Chen, V., Reggiardo, R. E., Millhauser, G. L., & Cone, R. D. (2018) · Journal of Neuroendocrinology · doi:10.1111/jne.12670 · Cited by 30 · see citing works
Falls, B. A., & Zhang, Y. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00346 · Cited by 30 · see citing works
A Brain-Melanocortin-Vagus Axis Mediates Adipose Tissue Expansion Independently of Energy Intake
Holland, J., Sorrell, J. E., Yates, E., Smith, K., Arbabi, S., Arnold, M., Rivir, M., Morano, R. L., Chen, J., Zhang, X., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.089 · Cited by 28 · see citing works
Recent Advances in Hypertension
Oliveira, V., Kwitek, A. E., Sigmund, C. D., Morselli, L. L., & Grobe, J. L. (2021) · Hypertension · doi:10.1161/hypertensionaha.120.14513 · Cited by 29 · see citing works
Milbank, E., Martínez, M. C., & Andriantsitohaina, R. (2015) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2015.11.002 · Cited by 29 · 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
The thermoneutral zone in women takes an “arctic” shift compared to men
Brychta, R. J., McGehee, S., Huang, S., Leitner, B. P., Duckworth, C. J., Fletcher, L. A., Kim, K., Cassimatis, T. M., Israni, N. S., Lea, H. J., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2311116121 · Cited by 28 · see citing works
Temporal cAMP Signaling Selectivity by Natural and Synthetic MC4R Agonists
Molden, B., Cooney, K. A., West, K. L., der Ploeg, L. H. T. V., & Baldini, G. (2015) · Molecular Endocrinology · doi:10.1210/me.2015-1071 · Cited by 27 · see citing works
Structural Complexity and Plasticity of Signaling Regulation at the Melanocortin-4 Receptor
Kleinau, G., Heyder, N., Tao, Y., & Scheerer, P. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165728 · Cited by 27 · see citing works
Bacterial Protein Mimetic of Peptide Hormone as a New Class of Protein- based Drugs
Fetissov, S. O., Legrand, R., & Lucas, N. (2018) · Current Medicinal Chemistry · doi:10.2174/0929867324666171005110620 · Cited by 26 · see citing works
The central melanocortin system as a treatment target for obesity and diabetes: A brief overview
Goit, R. K., Taylor, A. W., & Lo, A. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.174956 · Cited by 22 · see citing works
Alterations in GLP-1 and PYY release with aging and body mass in the human gut
Jones, L. A., Sun, E. W. L., Lumsden, A. L., Thorpe, D. W., Peterson, R. A., de Fontgalland, D., Sposato, L., Rabbitt, P., Hollington, P., Wattchow, D. A., et al. (2023) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2023.112072 · Cited by 21 · see citing works
Jacobsen, J. M., Petersen, N., Torz, L., Gerstenberg, M. K., Pedersen, K., Østergaard, S., Wulff, B. S., Andersen, B., Raun, K., Christoffersen, B. Ø., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.114501 · Cited by 21 · see citing works
The Fight Against Obesity Escalates: New Drugs on the Horizon and Metabolic Implications
Tsilingiris, D., Liatis, S., Dalamaga, Μ., & Kokkinos, A. D. (2020) · Current Obesity Reports · doi:10.1007/s13679-020-00378-x · Cited by 22 · see citing works
Papathanasiou, A. E., Nolen-Doerr, E., Farr, O. M., & Mantzoros, C. S. (2019) · European Journal of Endocrinology · doi:10.1530/eje-18-0847 · Cited by 20 · see citing works
The renin–angiotensin system in the arcuate nucleus controls resting metabolic rate
Deng, G., & Grobe, J. L. (2018) · Current Opinion in Nephrology & Hypertension · doi:10.1097/mnh.0000000000000477 · Cited by 20 · see citing works
Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism
Minakova, E., Lang, J., Medel‐Matus, J., Gould, G. G., Reynolds, A., Shin, D. H., Mazarati, A. M., & Sankar, R. (2019) · PLoS ONE · doi:10.1371/journal.pone.0210389 · Cited by 20 · see citing works
Circulating leptin levels are associated with adiposity in survivors of childhood brain tumors
Sims, E. D., Jennings, W. J., Empringham, B., Fleming, A. J., Portwine, C., Johnston, D. L., Zelcer, S. M., Rassekh, S. R., Burrow, S., Thabane, L., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-61520-2 · Cited by 21 · see citing works
Abawi, O., Koster, E. C., Welling, M. S., Boeters, S. C. M., van Rossum, E. F. C., van Haelst, M. M., van der Voorn, B., de Groot, C. J., & van den Akker, E. L. T. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.862817 · Cited by 19 · see citing works
Endogenous cannabinoids are required for MC4R-mediated control of energy homeostasis
Yong, Y., Çakır, I., Pan, P. L., Biddinger, J. E., Bluett, R. J., Mackie, K., Bingham, N. C., Patel, S. H., & Ghamari‐Langroudi, M. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2015990118 · Cited by 18 · see citing works
Recent progress in the pharmacotherapy for obesity
Lu, J., Liu, P., Cai, M., Lv, T., Zhang, M., Yin, K., Cheng, J., & Zhang, G. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.177850 · Cited by 17 · see citing works
A Gut-Intrinsic Melanocortin Signaling Complex Augments L-Cell Secretion in Humans
Sun, E. W. L., Iepsen, E. W., Pezos, N., Lumsden, A. L., Martin, A. M., Schober, G., Isaacs, N. J., Rayner, C. K., Nguyen, N. Q., de Fontgalland, D., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.04.014 · Cited by 17 · see citing works
White, A. M., Dellsèn, A., Larsson, N., Kaas, Q., Jansen, F., Plowright, A. T., Knerr, L., Durek, T., & Craik, D. J. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00793 · Cited by 17 · see citing works
The melanocortin‐4 receptor pathway and the emergence of precision medicine in obesity management
Fansa, S., & Acosta, A. J. (2024) · Diabetes Obesity and Metabolism · doi:10.1111/dom.15555 · Cited by 17 · see citing works
Energy expenditure due to gluconeogenesis in pathological conditions of insulin resistance
Quaye, E. M., Chacko, S. K., Chung, S. T., Brychta, R. J., Chen, K. Y., & Brown, R. J. (2021) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00281.2021 · Cited by 17 · see citing works
Ferrulli, A., Terruzzi, I. M., Senesi, P., Succi, M., Cannavaro, D., & Luzi, L. (2022) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2022.02.016 · Cited by 16 · see citing works
Doering, S. R., Freeman, K. T., Schnell, S. M., Haslach, E. M., Dirain, M. L. S., Debevec, G., Geer, P., Santos, R. G., Giulianotti, M. A., Pinilla, C., et al. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.7b00301 · Cited by 16 · see citing works
Santos, J. L., & Cortés, V. (2020) · Obesity Reviews · doi:10.1111/obr.13114 · Cited by 19 · see citing works
Design of cyclized selective melanotropins
Cai, M., & Hruby, V. J. (2016) · Biopolymers · doi:10.1002/bip.22976 · Cited by 15 · see citing works
Mutations in melanocortin-4 receptor: From fish to men
Tao, Y. (2022) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2022.03.003 · Cited by 14 · see citing works
Lazareva, J., Brady, S. M., & Yanovski, J. A. (2023) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2023.2199152 · Cited by 14 · see citing works
Thyroid Hormone Effects on Glucose Disposal in Patients With Insulin Receptor Mutations
Kushchayeva, Y. S., Startzell, M. S., Cochran, E. K., Auh, S., Sekizkardes, H., Soldin, S. J., Kushchayev, S. V., Dieckmann, W., Skarulis, M. C., Sater, Z. A., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgz079 · Cited by 15 · see citing works
Beyond satiety: unraveling the complex roles of POMC neurons in behavior and metabolism
Jouque, V., Miralpeix, C., López-Gambero, A. J., Nicolas, J. C., Quarta, C., & Cota, D. (2025) · Reviews in Endocrine and Metabolic Disorders · doi:10.1007/s11154-025-09993-2 · Cited by 13 · see citing works
Setmelanotide for the Treatment of Acquired Hypothalamic Obesity
Miller, J. L., van Santen, H. M., Phillips, S. A., Hamilton, J., Aberle, J., Sathyapalan, T., Mohamed, Z., McCormack, S. E., Shoemaker, A. H., Kelsey, M. M., et al. (2026) · New England Journal of Medicine · doi:10.1056/nejmoa2512275 · Cited by 13 · see citing works
- Authors
- Chen, K. Y., Muniyappa, R., Abel, B. S., Mullins, K. P., Staker, P., Brychta, R. J., Zhao, X., Ring, M., Psota, T. L., Cone, R. D., Panaro, B. L., Gottesdiener, K. M., Van der Ploeg, L. H. T., Reitman, M. L., & Skarulis, M. C.
- Affiliations
- National Institutes of Health (US)
- Vanderbilt University (US)
- Rhythm (United states) (US)
- Rhythm Pharmaceuticals (K.M.G., L.H.T.V.d.P.), Boston, Massachusetts 02116
- Corresponding author
- Skarulis, Monica C.
- ORCID
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2015-04-01
- Volume
- 100
- Issue
- 4
- Pages
- 1639-1645
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC4399297
- OpenAlex
- W2079643489
- Cited by
- 174
- References
- 30
- Citations by year
- 2026: 4 · 2025: 13 · 2024: 11 · 2023: 8 · 2022: 13 · 2021: 21 · 2020: 22 · 2019: 21 · 2018: 21 · 2017: 16 · 2016: 18 · 2015: 6
- FWCI
- 11.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (MD 20892)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK070332, P30DK058404)
- NIH Clinical Center
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- melanocortin-4 receptor agonist, resting energy expenditure, obesity, energy expenditure, substrate oxidation, respiratory quotient, weight loss, continuous subcutaneous infusion, thermogenesis
- MeSH terms
- Adult, alpha-MSH, Combined Modality Therapy, Double-Blind Method, Energy Metabolism, Female, Humans, Male, Middle Aged, Obesity, Rest, Cross-Over Studies, Anti-Obesity Agents, Receptor, Melanocortin, Type 4, Young Adult, Weight Reduction Programs
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
