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Obesity due to melanocortin 4 receptor deficiency

MedGen UID:
903905
•Concept ID:
C4273958
•
Disease or Syndrome
Synonyms: MC4R deficiency; obesity due to melanocortin 4 receptor deficiency
SNOMED CT: Obesity due to melanocortin 4 receptor deficiency (717269008)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
•Concept ID:
C0441748
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
•Concept ID:
C0443147
•
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
Autosomal recessive inheritance (Orphanet)
Autosomal dominant inheritance (Orphanet)
 
Monarch Initiative: MONDO:0019115
Orphanet: ORPHA71529

Definition

Melanocortin 4 receptor (MC4R) deficiency is the commonest form of monogenic obesity identified so far. MC4R deficiency is characterised by severe obesity, an increase in lean body mass and bone mineral density, increased linear growth in early childhood, hyperphagia beginning in the first year of life and severe hyperinsulinaemia, in the presence of preserved reproductive function. MC4R is a G protein-coupled receptor involved in the hypothalamic leptin-melanocortin signalling pathway. Activation of the MC4R plays a key role in the maintenance of energy homeostasis and is associated with suppression of food intake. [from SNOMEDCT_US]

Professional guidelines

PubMed

Long-Term MC4R Agonist Treatment in POMC-Deficient Patients.
Kühnen P, Clément K
N Engl J Med 2022 Sep 1;387(9):852-854. doi: 10.1056/NEJMc2207442. PMID: 36053514
Melanocortin-4 Receptor Signalling: Importance for Weight Regulation and Obesity Treatment.
Kühnen P, Krude H, Biebermann H
Trends Mol Med 2019 Feb;25(2):136-148. Epub 2019 Jan 11 doi: 10.1016/j.molmed.2018.12.002. PMID: 30642682
The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options.
Fani L, Bak S, Delhanty P, van Rossum EF, van den Akker EL
Int J Obes (Lond) 2014 Feb;38(2):163-9. Epub 2013 Jun 18 doi: 10.1038/ijo.2013.80. PMID: 23774329

Recent clinical studies

Etiology

Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with delayed gastric emptying.
Seelig E, Henning E, Keogh JM, Gillett D, Shin E, Buscombe J, van der Klaauw AA, Farooqi IS
Clin Endocrinol (Oxf) 2022 Feb;96(2):270-275. Epub 2021 Oct 25 doi: 10.1111/cen.14615. PMID: 34694010
Obesity, kidney dysfunction, and inflammation: interactions in hypertension.
Hall JE, Mouton AJ, da Silva AA, Omoto ACM, Wang Z, Li X, do Carmo JM
Cardiovasc Res 2021 Jul 7;117(8):1859-1876. doi: 10.1093/cvr/cvaa336. PMID: 33258945Free PMC Article
Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials.
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Melanocortin-4 Receptor Signalling: Importance for Weight Regulation and Obesity Treatment.
Kühnen P, Krude H, Biebermann H
Trends Mol Med 2019 Feb;25(2):136-148. Epub 2019 Jan 11 doi: 10.1016/j.molmed.2018.12.002. PMID: 30642682
Fructose: should we worry?
Bray GA
Int J Obes (Lond) 2008 Dec;32 Suppl 7:S127-31. doi: 10.1038/ijo.2008.248. PMID: 19136981

Diagnosis

CRTC1 deficiency, specifically in melanocortin-4 receptor-expressing cells, induces hyperphagia, obesity, and insulin resistance.
Matsumura S, Miyakita M, Miyamori H, Kyo S, Ishikawa F, Sasaki T, Jinno T, Tanaka J, Fujita K, Yokokawa T, Goto T, Momma K, Takenaka S, Inoue K
FASEB J 2022 Dec;36(12):e22645. doi: 10.1096/fj.202200617R. PMID: 36349991
Obesity Due to Steroid Receptor Coactivator-1 Deficiency Is Associated With Endocrine and Metabolic Abnormalities.
Cacciottolo TM, Henning E, Keogh JM, Bel Lassen P, Lawler K, Bounds R, Ahmed R, Perdikari A, Mendes de Oliveira E, Smith M, Godfrey EM, Johnson E, Hodson L, Clément K, van der Klaauw AA, Farooqi IS
J Clin Endocrinol Metab 2022 May 17;107(6):e2532-e2544. doi: 10.1210/clinem/dgac067. PMID: 35137184Free PMC Article
Obesity-Associated GNAS Mutations and the Melanocortin Pathway.
Mendes de Oliveira E, Keogh JM, Talbot F, Henning E, Ahmed R, Perdikari A, Bounds R, Wasiluk N, Ayinampudi V, Barroso I, Mokrosiński J, Jyothish D, Lim S, Gupta S, Kershaw M, Matei C, Partha P, Randell T, McAulay A, Wilson LC, Cheetham T, Crowne EC, Clayton P, Farooqi IS
N Engl J Med 2021 Oct 21;385(17):1581-1592. Epub 2021 Oct 6 doi: 10.1056/NEJMoa2103329. PMID: 34614324
Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.
Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, Henning E, Poitou-Bernert C, Oppert JM, Tounian P, Marchelli F, Alili R, Le Beyec J, Pépin D, Lacorte JM, Gottesdiener A, Bounds R, Sharma S, Folster C, Henderson B, O'Rahilly S, Stoner E, Gottesdiener K, Panaro BL, Cone RD, Clément K, Farooqi IS, Van der Ploeg LHT
Mol Metab 2017 Oct;6(10):1321-1329. Epub 2017 Jul 8 doi: 10.1016/j.molmet.2017.06.015. PMID: 29031731Free PMC Article
Melanocortin-4 receptor mutations in obesity.
Santini F, Maffei M, Pelosini C, Salvetti G, Scartabelli G, Pinchera A
Adv Clin Chem 2009;48:95-109. PMID: 19803416

Therapy

The melanocortin pathway and energy homeostasis: From discovery to obesity therapy.
Yeo GSH, Chao DHM, Siegert AM, Koerperich ZM, Ericson MD, Simonds SE, Larson CM, Luquet S, Clarke I, Sharma S, Clément K, Cowley MA, Haskell-Luevano C, Van Der Ploeg L, Adan RAH
Mol Metab 2021 Jun;48:101206. Epub 2021 Mar 6 doi: 10.1016/j.molmet.2021.101206. PMID: 33684608Free PMC Article
Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials.
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.
Collet TH, Dubern B, Mokrosinski J, Connors H, Keogh JM, Mendes de Oliveira E, Henning E, Poitou-Bernert C, Oppert JM, Tounian P, Marchelli F, Alili R, Le Beyec J, Pépin D, Lacorte JM, Gottesdiener A, Bounds R, Sharma S, Folster C, Henderson B, O'Rahilly S, Stoner E, Gottesdiener K, Panaro BL, Cone RD, Clément K, Farooqi IS, Van der Ploeg LHT
Mol Metab 2017 Oct;6(10):1321-1329. Epub 2017 Jul 8 doi: 10.1016/j.molmet.2017.06.015. PMID: 29031731Free PMC Article
Monogenic human obesity.
Farooqi IS
Front Horm Res 2008;36:1-11. doi: 10.1159/000115333. PMID: 18230891
Monogenic obesity in humans.
Farooqi IS, O'Rahilly S
Annu Rev Med 2005;56:443-58. doi: 10.1146/annurev.med.56.062904.144924. PMID: 15660521

Prognosis

Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis.
Xu B, Lawler K, Wyler SC, Li L, Swati, Keogh JM, Chen X, Wan R, Almeida AG, Kirsch S, Mountjoy KG, Elmquist JK, Farooqi IS, Liu C
Sci Transl Med 2025 Jan 15;17(781):eadr6459. doi: 10.1126/scitranslmed.adr6459. PMID: 39813316Free PMC Article
Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials.
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Updates on Monogenic Obesity in a Multifactorial Disease.
Baxter J, Armijo PR, Flores L, Krause C, Samreen S, Tanner T
Obes Surg 2019 Dec;29(12):4077-4083. doi: 10.1007/s11695-019-04200-z. PMID: 31641982
Obesity due to melanocortin 4 receptor (MC4R) deficiency is associated with increased linear growth and final height, fasting hyperinsulinemia, and incompletely suppressed growth hormone secretion.
Martinelli CE, Keogh JM, Greenfield JR, Henning E, van der Klaauw AA, Blackwood A, O'Rahilly S, Roelfsema F, Camacho-Hübner C, Pijl H, Farooqi IS
J Clin Endocrinol Metab 2011 Jan;96(1):E181-8. Epub 2010 Nov 3 doi: 10.1210/jc.2010-1369. PMID: 21047921
Monogenic obesity in humans.
Farooqi IS, O'Rahilly S
Annu Rev Med 2005;56:443-58. doi: 10.1146/annurev.med.56.062904.144924. PMID: 15660521

Clinical prediction guides

Orthopedia regulates melanocortin 4 receptor transcription and energy homeostasis.
Xu B, Lawler K, Wyler SC, Li L, Swati, Keogh JM, Chen X, Wan R, Almeida AG, Kirsch S, Mountjoy KG, Elmquist JK, Farooqi IS, Liu C
Sci Transl Med 2025 Jan 15;17(781):eadr6459. doi: 10.1126/scitranslmed.adr6459. PMID: 39813316Free PMC Article
Obesity-Associated GNAS Mutations and the Melanocortin Pathway.
Mendes de Oliveira E, Keogh JM, Talbot F, Henning E, Ahmed R, Perdikari A, Bounds R, Wasiluk N, Ayinampudi V, Barroso I, Mokrosiński J, Jyothish D, Lim S, Gupta S, Kershaw M, Matei C, Partha P, Randell T, McAulay A, Wilson LC, Cheetham T, Crowne EC, Clayton P, Farooqi IS
N Engl J Med 2021 Oct 21;385(17):1581-1592. Epub 2021 Oct 6 doi: 10.1056/NEJMoa2103329. PMID: 34614324
Eating behaviour in contrasting adiposity phenotypes: Monogenic obesity and congenital generalized lipodystrophy.
Santos JL, Cortés VA
Obes Rev 2021 Jan;22(1):e13114. Epub 2020 Aug 2 doi: 10.1111/obr.13114. PMID: 33030294
Efficacy and safety of setmelanotide, an MC4R agonist, in individuals with severe obesity due to LEPR or POMC deficiency: single-arm, open-label, multicentre, phase 3 trials.
Clément K, van den Akker E, Argente J, Bahm A, Chung WK, Connors H, De Waele K, Farooqi IS, Gonneau-Lejeune J, Gordon G, Kohlsdorf K, Poitou C, Puder L, Swain J, Stewart M, Yuan G, Wabitsch M, Kühnen P; Setmelanotide POMC and LEPR Phase 3 Trial Investigators
Lancet Diabetes Endocrinol 2020 Dec;8(12):960-970. Epub 2020 Oct 30 doi: 10.1016/S2213-8587(20)30364-8. PMID: 33137293
Monogenic human obesity syndromes.
Farooqi IS, O'Rahilly S
Recent Prog Horm Res 2004;59:409-24. doi: 10.1210/rp.59.1.409. PMID: 14749512

Recent systematic reviews

The melanocortin-4 receptor as target for obesity treatment: a systematic review of emerging pharmacological therapeutic options.
Fani L, Bak S, Delhanty P, van Rossum EF, van den Akker EL
Int J Obes (Lond) 2014 Feb;38(2):163-9. Epub 2013 Jun 18 doi: 10.1038/ijo.2013.80. PMID: 23774329

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