Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques
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The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects.
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Administration of RM-493 (setmelanotide) caused transient decreases in food intake (35%) in a diet-induced obese nonhuman primate model.
“Kievit et al [78] reported that administration of another small peptide MC4R agonist, RM-493 (also known as BIM-22493 or setmelanotide), caused transient decreases in food intake (35%) with persistent weight loss and no significant increases in BP or HR over 8 weeks of treatment in a diet-induced obese nonhuman primate model.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [78]
Administration of RM-493 caused persistent weight loss in a diet-induced obese nonhuman primate model.
“Kievit et al [78] reported that administration of another small peptide MC4R agonist, RM-493 (also known as BIM-22493 or setmelanotide), caused transient decreases in food intake (35%) with persistent weight loss and no significant increases in BP or HR over 8 weeks of treatment in a diet-induced obese nonhuman primate model.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [78]
Administration of RM-493 caused no significant increases in blood pressure or heart rate over 8 weeks in a diet-induced obese nonhuman primate model.
“Kievit et al [78] reported that administration of another small peptide MC4R agonist, RM-493 (also known as BIM-22493 or setmelanotide), caused transient decreases in food intake (35%) with persistent weight loss and no significant increases in BP or HR over 8 weeks of treatment in a diet-induced obese nonhuman primate model.”
From Role of the brain melanocortins in blood pressure regulation (2017) · cites this paper as [78]
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- Authors
- 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.
- Affiliations
- Oregon National Primate Research Center (US)
- Ipsen (United States) (US)
- Oregon Health & Science University (US)
- Corresponding author
- Grove, Kevin L.
- Culler, Michael D.
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2013-01-17
- Volume
- 62
- Issue
- 2
- Pages
- 490-497
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3554387
- OpenAlex
- W2167727277
- Cited by
- 231
- References
- 45
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 13 · 2023: 16 · 2022: 15 · 2021: 22 · 2020: 14 · 2019: 17 · 2018: 18 · 2017: 16 · 2016: 12 · 2015: 19 · 2014: 36 · 2013: 8 · 2012: 2
- FWCI
- 9.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (OD 011092-53, P51OD011092)
- National Center for Research Resources (P51RR000163)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Pharmacology › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- melanocortin-4 receptor, MC4R agonist, diet-induced obesity, rhesus monkeys, weight loss, insulin resistance, glucose tolerance, cardiovascular function, blood pressure, heart rate, dietary intake, obesity pharmacotherapy, adverse drug reactions
- MeSH terms
- alpha-MSH, Animals, Blood Pressure, Cardiovascular System, Chronic Disease, Eating, Heart Rate, Insulin Resistance, Macaca mulatta, Male, Obesity, Peptides, Weight Loss, Glucose Intolerance, Anti-Obesity Agents, Receptor, Melanocortin, Type 4, Adiposity, Diet, High-Fat
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