The DOI matches its Crossref record; 57 of the 59 references it cites were found in a registry or an index.
Patients with Obesity Caused by Melanocortin-4 Receptor Mutations Can Be Treated with a Glucagon-like Peptide-1 Receptor Agonist
Open accessAbstract
Pathogenic mutations in the appetite-regulating melanocortin-4 receptor (MC4R) represent the most common cause of monogenic obesity with limited treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause weight loss by reducing appetite. We assessed the effect of the GLP-1 RA liraglutide 3.0 mg for 16 weeks in 14 obese individuals with pathogenic MC4R mutations (BMI 37.5 ± 6.8) and 28 matched control participants without MC4R mutation (BMI 36.8 ± 4.8). Liraglutide decreased body weight by 6.8 kg ± 1.8 kg in individuals with pathogenic MC4R mutations and by 6.1 kg ± 1.2 kg in control participants. Total body fat, waist circumference, and fasting and postprandial glucose concentrations similarly decreased in both groups. Thus, liraglutide induced an equal, clinically significant weight loss of 6% in both groups, indicating that the appetite-reducing effect of liraglutide is preserved in MC4R causal obesity and that liraglutide acts independently of the MC4R pathway. Thus, liraglutide could be an effective treatment of the most common form of monogenic obesity.
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“Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, is used in the treatment of obesity because it induces weight loss 21-23 and maintains low-calorie diet-induced weight loss for at least 1 year, 11,24 primarily by means of appetite inhibition. 25”
From Healthy Weight Loss Maintenance with Exercise, Liraglutide, or Both Combined (2021) · cites this paper as [23]
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“Short-term studies have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RA) induce weight loss by promoting satiety and reducing hunger16–19.”
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“there is evidence from a small clinical study with liraglutide20 that they may be effective in people with MC4R deficiency.”
From Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency (2025) · cites this paper as [20]
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Citations
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“To the best of our knowledge liraglutide effects on morbid obesity were described in 7 PWS patients all affected also by T2DM (15–18) and in a prospective case-control nonrandomized study on 14 patients affected by monogenic obesity related to melanocortin-4 receptor (MC4R) mutations (19).”
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Kühnen, P., Argente, J., Clément, K., Dollfus, H., Dubern, B., Farooqi, I. S., de Groot, C., Grüters, A., Holm, J., Hopkins, M., et al. (2024) · Clinical Obesity · doi:10.1111/cob.12659 · Cited by 2
“47 In summary, obesity needs to be managed as a chronic disease, based on the understanding that it is driven by fat (energy) regulation, which disqualifies several commonly believed concepts such as motivation and caloric restriction.”
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Zorn, S., Schirmer, M., von Schnurbein, J., Brandt, S., Göpel, E., Stein, R., Wiegand, S., Körner, A., Kühnen, P., & Wabitsch, M. (2024) · Adipositas - Ursachen Folgeerkrankungen Therapie · doi:10.1055/a-2292-1830 · Cited by 2
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“Bunun yanında obez MC4R gen varyantı taşıyıcılarında glukagon benzeri bir peptit 1 reseptörü (GLP-1R) agonisti kullanılarak yapılan farmakolojik tedavi araştırılmaktadır (76).”
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Self-citationAngeborene Adipositasformen und Therapien
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“29 The hepatic expression of adenylate cyclase 3 is regulated, in mice, by liraglutide.”
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Obesity medication lorcaserin requires brainstem GLP-1 neurons to reduce food intake in micePreprint
Wagner, S., Brierley, D. I., Leeson-Payne, A. T. S., Jiang, W., Chianese, R., Lam, B., Dowsett, G. K. C., Cristiano, C., Lyons, D., Reimann, F. M., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.05.06.490598
“In contrast to lorcaserin, GLP-1R agonists liraglutide and exendin-4 did not require functional MC4Rs to impact feeding in mice (Figure 4a-b and Supplementary Figure 5g-h), which corroborates an earlier report in humans with MC4R mutations who were prescribed liraglutide (27).”
ResultMosbah, H., Faucher, P., Heide, S., Dubern, B., Clément, K., & Poitou, C. (2021) · Elsevier eBooks · doi:10.1016/b978-2-294-76753-1.00069-2
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“Since MC4R functions are affected by anorexigenic hormones, and GLP-1 receptor agonists (such as liraglutide) have been recommended as an effective treatment for the most common form of monogenic obesity caused by mutations in the MC4R gene(58), we might expect that exposure to high-protein diets may modulate MC4R met…”
BackgroundHenriksen, M., & Dai, Z. (2023) · Elsevier eBooks · doi:10.1016/b978-0-323-99269-5.00003-7
Schirmer, M., Brandt, S., Zorn, S., & Wabitsch, M. (2023) · Adipositas - Ursachen Folgeerkrankungen Therapie · doi:10.1055/a-2079-9133
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Nguyen, M. X., Danner, L., & Thaker, V. (2023) · Springer eBooks · doi:10.1007/978-3-031-37380-0_13
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Rajcsanyi, L. S., Schmidt, J., Düerkop, S., Grote, L., Peters, T., Körner, A., Fischer‐Posovszky, P., & Hinney, A. (2023) · Adipositas - Ursachen Folgeerkrankungen Therapie · doi:10.1055/a-2185-6864
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“Sono anche stati de-scritti casi di efficace trattamento dell’HO con liraglutide in pazienti con varianti patologiche di MC4-R, con mi-glioramento anche dei diversi parametri metabolici [27].”
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“In 2020, the FDA approved setmelanotide for treating obesity in adults and children aged six years and older with confirmed genetic diagnosis of POMC, PCSK1 and LEPR deficiencies, followed by the EMA in 2021 [35-37].”
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Anti-obesity Pharmacotherapy for Patients with Genetic Obesity Disorders
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“However, evidence in both acquired and genetic HO is scarce and based on small cohorts with variable designs and semaglutide dosage [19–26].”
Metabolic Roles of Acyl Coenzyme A-Binding Protein (ACBP)/Diazepam Binding Inhibitor (DBI)
Joseph, A. (2021) · theses.fr (ABES) · doi:10.70675/b045685ezd444z4b46zb0f9z0e726ceac466
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“Currently, limited evidence exists regarding the use of other GLP-1 analogs—e.g., semaglutide, dulaglutide, or dual agonists, such as tirzepatide—in monogenic obesity [13,14].”
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Feng, W., Zhou, Q., & Wang, M. (2026) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2026.06.035
“MC4R emerged as one of the most compelling targets because melanocortinergic appetite suppression acts at a downstream and mechanistically distinct node from GLP-1R signaling 72-74 .”
Weight Loss Following Liraglutide Therapy in a Patient With Smith-Magenis Syndrome: A Case Report
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“…evaluating liraglutide and semaglutide in monogenic obesity reveal a broad range of weight-loss outcomes, spanning from a modest 4.7% to an exceptional 29.3% reduction, the latter observed in a Bardet-Biedl syndrome case report utilizing sequential liraglutide and semaglutide therapy [8,14,15].”
InfluentialThe application of GLP-1 receptor agonists in obesity due to MC4R deficiency
Ding, M., Luo, Y., & Ji, L. (2026) · Metabolism and Target Organ Damage · doi:10.20517/mtod.2026.58
Li, X., Wang, X., Liu, X., Wang, S., & Yang, W. (2026) · Molecular Genetics & Genomic Medicine · doi:10.1002/mgg3.70276
“The majority of mutations in the MC4R gene are missense mutations (Iepsen et al. 2018), which are inherited in both dominant and recessive forms.”
Clément, K., Farooqi, I. S., Kühnen, P., Wabitsch, M., Cetiner, M., Argente, J., & Grueters, A. (2026) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgag330
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Pellitero, S., Baena, N., del Portillo, R. C., de Nanclares, G. P., Ramon‐Krauel, M., Bretón, I., & Caixàs, A. (2026) · Endocrinología Diabetes y Nutrición · doi:10.1016/j.endinu.2026.501922
Metadata
- Authors
- Iepsen, E. W., Zhang, J., Thomsen, H. S., Hansen, E. L., Hollensted, M., Madsbad, S., Hansen, T., Holst, J. J., Holm, J.-C., & Torekov, S. S.
- Affiliations
- University of Copenhagen (DK)
- Herlev Hospital (DK)
- Hvidovre Hospital (DK)
- Holbæk Sygehus (DK)
- Corresponding author
- Iepsen, Eva W.
- Torekov, Signe S.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 28
- Issue
- 1
- Pages
- 23-32.e3
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2806545464
- Cited by
- 156
- References
- 59
- Citations by year
- 2026: 18 · 2025: 15 · 2024: 25 · 2023: 24 · 2022: 22 · 2021: 21 · 2020: 22 · 2019: 6 · 2018: 3
- FWCI
- 7.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Lundbeckfonden
- Region Sjælland
- Danish Diabetes Academy
- Novo Nordisk Fonden
- Aase og Ejnar Danielsens Fond (NNF15CC0018486)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Pharmacology (medical) › Pharmacology and Obesity Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- melanocortin-4 receptor, MC4R mutations, monogenic obesity, liraglutide, GLP-1 receptor agonists, weight loss, appetite regulation, fat mass, fasting and postprandial glucose, obesity treatment
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Liraglutide, Adult, Appetite, Female, Humans, Hypoglycemic Agents, Male, Middle Aged, Mutation, Obesity, Weight Loss, Receptor, Melanocortin, Type 4
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