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Mechanism of Disease

Different obesity defined

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Understanding the role of the hypothalamic
MC4R pathway

The melanocortin-4 receptor (MC4R) pathway in the hypothalamus plays a critical role in energy balance and body weight regulation. The key distinguishing symptoms of MC4R pathway impairment include hyperphagia and obesity.1,2

General obesity and MC4R pathway–driven obesity are not the same

General Obesity3,4

Occurrence: Can occur at any age, including later in life.

Cause: Interaction of multiple factors, including:

  • Age, race, or gender
  • Concurrent illnesses
  • Common genetic variants
  • Concomitant medications
  • Environmental factors
  • Nutrition and physical activity
MC4R Pathway–Driven Obesity1,2,5–8

Occurrence:

  • With genetic diseases, MC4R pathway impairment is present at birth, leading to early-onset obesity
  • With acquired forms, impairment of the pathway will follow injury or trauma to the hypothalamus, leading to accelerated and sustained weight gain

Cause: Impairment of the MC4R pathway, leading to:

  • Hyperphagia (chronic pathological condition characterized by insatiable hunger, impaired satiety, and persistent abnormal food-seeking behaviors)
  • Obesity (early-onset for genetic form or rapid-onset for acquired)
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Hyperphagia severity can vary

Hyperphagia is often differentiated from other types of overeating by its severity and persistence. However, the presentation of symptoms and behaviors can vary in severity from patient to patient and based on the underlying disease.2,9

Hyperphagia in
Bardet-Biedl syndromeHyperphagia in acquired hypothalamic obesity

Downloadable

Recognize different obesity. Take action and screen your patients. Identify hyperphagia in your patients who may have MC4R pathway impairment.
Hyperphagia questionnaire thumbnail

Download Questionnaire

Causes of MC4R pathway impairment

Knowing the cause of your patient's different obesity and hunger may
help manage long-term health outcomes and alleviate patient burden.1,2,10
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Acquired5-8

  • Injury to the hypothalamus can disrupt MC4R pathway signaling, ultimately leading to accelerated and sustained weight gain

Explore acquired
hypothalamic obesity

Genetic1,2

  • Some gene variants can result in a rare genetic disease and lead to impairment of MC4R pathway signaling. While symptoms can vary depending on whether it is syndromic or monogenic, MC4R pathway impairment due to genetic variants can lead to hyperphagia and early-onset obesity

Learn about Bardet-Biedl syndrome

Understand monogenic obesity

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Why having a diagnosis matters

Obesity due to MC4R pathway impairment requires a distinct diagnosis and tailored management compared with the management of general obesity.

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Role of the hypothalamus and MC4R pathway

The MC4R pathway in the hypothalamus is a key signaling pathway in regulating
hunger, satiety, energy expenditure, and ultimately, weight3,11–14
The MC4R pathway plays a key role in regulating hunger, which involves neural activation within the hypothalamic region in response to leptin release. Leptin binding to the LEPR triggers a signaling cascade that includes the secretion of alpha-melanocyte-stimulating hormone from the POMC neuron that binds to the MC4 receptor. This activation of the MC4R pathway regulates hunger, satiety, and energy expenditure, so weight and energy remain in balance.

Impairment in the MC4R pathway

MC4R pathway impairment disrupts MC4R pathway signaling, ultimately leading to
hyperphagia and decreased energy expenditure, resulting in weight gain1,3,11–16
A variant in one or more genes can impair the MC4R pathway in the hypothalamus, leading to disruption of satiety signaling. Alpha-melanocyte-stimulating hormone production is impaired or deficient, which prevents activation of the MC4 receptor and impairment of the MC4R pathway. This leads to decreased satiety signaling, hyperphagia, and reduced energy expenditure, all of which can lead to a different obesity.

POMC=Proopiomelanocortin

Acquired Hypothalamic Obesity
References
  1. Eneli I, Xu J, Webster M, et al. Tracing the effect of the melanocortin-4 receptor pathway in obesity: study design and methodology of the TEMPO registry. Appl Clin Genet. 2019 Jun 5;12:87-93. doi:10.2147/TACG.S199092
  2. Hampl SE, Hassink SG, Skinner AC, et al. Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics. 2023;151(2):e2022060640. doi:10.1542/peds.2022-060640
  3. Huvenne H, Dubern B, Clément K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obes Facts. 2016;9(3):158-173. doi:10.1159/000445061
  4. Tondt J, Freshwater M, Afreen S, et al. Obesity Algorithm 2023. Obesity Medicine Association; 2023. Accessed January 7, 2025. https://obesitymedicine.org/obesity-algorithm
  5. Abuzzahab MJ, Roth CL, Shoemaker AH. Hypothalamic obesity: prologue and promise. Horm Res Paediatr. 2019;91(2):128-136. doi:10.1159/000496564
  6. Roth CL. Hypothalamic obesity in patients with craniopharyngioma: profound changes of several weight regulatory circuits. Front Endocrinol (Lausanne). 2011;2:49. doi:10.3389/fendo.2011.00049
  7. Roth CL, Enriori PJ, Gebhardt U, et al. Changes of peripheral alpha-melanocyte-stimulating hormone in childhood obesity. Metabolism. 2010;59(2):186-194. doi:10.1016/j.metabol.2009.06.031
  8. Roth CL, Gebhardt U, Müller HL. Appetite-regulating hormone changes in patients with craniopharyngioma. Obesity (Silver Spring). 2011;19(1):36-42. doi:10.1038/oby.2010.80
  9. Heymsfield SB, Clément K, Dubern B, et al. Defining hyperphagia for improved diagnosis and management of MC4R pathway-associated disease: a roundtable summary. Curr Obes Rep. 2025;14(1):13. Published 2025 Jan 25. doi:10.1007/s13679-024-00601-z
  10. Manara E, Paolacci S, D'Esposito F, et al. Mutation profile of BBS genes in patients with Bardet-Biedl syndrome: an Italian study. Ital J Pediatr. 2019;45(1):72. Published 2019 Jun 13. doi:10.1186/s13052-019-0659-1
  11. da Fonseca ACP, Mastronardi C, Johar A, Arcos-Burgos M, Paz-Filho G. Genetics of non-syndromic childhood obesity and the use of high-throughput DNA sequencing technologies. J Diabetes Complications. 2017;31(10):1549-1561. doi:10.1016/j.jdiacomp.2017.04.026
  12. Yazdi FT, Clee SM, Meyre D. Obesity genetics in mouse and human: back and forth, and back again. PeerJ. 2015 Mar 24;3:e856. doi:10.7717/peerj.856
  13. Burns B, Schmidt K, Williams SR, Kim S, Girirajan S, Elsea SH. Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome. Hum Mol Genet. 2010;19(20):4026-4042. doi:10.1093/hmg/ddq317
  14. Lu Q, Yang Y, Jia S, et al. SRC1 deficiency in hypothalamic arcuate nucleus increases appetite and body weight. J Mol Endocrinol. Published online October 1, 2018. doi:10.1530/JME-18-0075
  15. Blaess S, Wachten D. The BBSome: a nexus controlling energy metabolism in the brain. J Clin Invest. 2021;131(8):e148903. doi:10.1172/JCI148903
  16. Seo S, Guo DF, Bugge K, Morgan DA, Rahmouni K, Sheffield VC. Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling. Hum Mol Genet. 2009;18(7):1323-1331. doi:10.1093/hmg/ddp031

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