What is the MC4R pathway?
The MC4R pathway plays a key role in the regulation of energy homeostasis. Variants in genes in the MC4R pathway or injury to the hypothalamic region may lead to impaired or deficient alpha-melanocyte-stimulating hormone (α-MSH) production. This can adversely affect MC4R pathway signaling, causing hyperphagia (pathological, insatiable hunger and impaired satiety accompanied by abnormal food-seeking behaviors) and decreased energy expenditure, which may lead to severe obesity.11-13,20,22,24
Watch this video to learn more about the role of rare gene variants in MC4R pathway signaling.
Obesity is not one disease, but many diseases4,10,12
General obesity4
Rare MC4R pathway disease
Acquired hypothalamic obesity
Rare genetic variants
An acquired form of accelerated and sustained weight gain that occurs most frequently after hypothalamic damage (eg, resulting from surgical resection or radiation of brain tumors).21,24
Monogenic obesity:
Obesity due to variants in single genes.9 Examples include POMC deficiency and LEPR deficiency, which are caused by variants in POMC or PCSK1 and LEPR, respectively.2,14
Syndromic obesity:
Understanding the root cause(s) of obesity is essential for early diagnosis and optimal disease management, particularly unique obesities caused by MC4R pathway impairment, which may require specialized management strategies.7,10,18
Discover more
Discover recommendations for suspecting patients with rare MC4R pathway diseases.
α-MSH, alpha-melanocyte-stimulating hormone; BBS, Bardet-Biedl syndrome; LEPR, leptin receptor gene; MC4R, melanocortin-4 receptor; POMC, proopiomelanocortin gene; PCSK1, proprotein convertase subtilisin/kexin type 1 gene
References
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- Fitch AK, Malhotra S, Conroy R. Differentiating monogenic and syndromic obesities from polygenic obesity: Assessment, diagnosis, and management. Obes Pillars. 2024 Apr 22;11:100110. doi: 10.1016/j.obpill.2024.100110. PMID: 38766314; PMCID: PMC11101890.
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- Mayo Clinic. https://www.mayoclinic.org/diseases-conditions/obesity/symptoms-causes/syc-20375742. Accessed February 21, 2024.
- Muñoz Yáñez et al. Austin Journal of Nutrition and Metabolism. 2017;4:1052.
- Pigeyre M, Yazdi FT, Kaur Y, Meyre D. Recent progress in genetics, epigenetics and metagenomics unveils the pathophysiology of human obesity. Clin Sci (Lond). 2016;130(12):943-986.
- Poitou C, et al. Eur J Endocrinol. Nov 2020;183(5):R149-r166.
- Pomeroy J, et al. Pediatr Obes. 2021;16(2):e12703.
- Rose SR, et al. Obesity (Silver Spring). 2018;26(11):1727-1732.
- Roth CL, McCormack SE. Diabetes Obes Metab. 2024;26(suppl 2):34-45.
- Sherafat-Kazemzadeh R, Ivey L, Kahn SR, et al. Hyperphagia among patients with Bardet-Biedl syndrome. Pediatr Obes. 2013;8(5):e64-e67.
- Speliotes et al. Nat Genet. 2010;42:937-948.
- Van Iersel L, et al. Endocr Rev. 2019;40(1):193-235.
