Rare genetic mutations can cause obesity

Several rare disorders of obesity are caused by genetic mutations that lead to dysfunction within a key pathway responsible for regulating hunger: the melanocortin-4 receptor (MC4R) pathway.1,2 Dysfunction within this pathway is implicated in several rare genetic disorders of obesity, including POMC and LEPR deficiency as well as previously characterized obesity syndromes such as Prader-Willi syndrome.2,3 The estimated prevalence of some of these disorders is shown below.

Estimated prevalence*

Prevalence of obesity disorders in the U.S. caused by rare genetic mutatations

In cases of rare genetic disorders of obesity, severe obesity persists despite diet and lifestyle modifications.4

Distracted by food, man with insatiable hunger in office


Genes within the MC4R pathway are responsible for regulating hunger, which involves neural activation within the hypothalamic region of the brain in response to leptin release from adipose tissue. Proper regulation of hunger requires sufficient levels of melanocyte-stimulating hormone (MSH) neuropeptides that activate MC4R, triggering a reduction in hunger and concomitant increase in energy expenditure.1,2,5

Dysfunction in the MC4R pathway can lead to obesity

In some patients, rare genetic mutations lead to a loss of function in factors upstream of MC4R (eg, LEPR, POMC, and proprotein convertase subtilisin/kexin type 1 [PCSK1]) and can result in insufficient levels of functional MSH neuropeptides, ultimately causing dysfunctional regulation of hunger that can lead to insatiable hunger and obesity.6

NeuropeptideSignal (MSH) Defect inUpstream Genetic Factors(e.g., POMC, LEPR, PCSK1) DYSFUNCTIONAL DownstreamActivation NeuropeptideSignal (MSH) Upstream Genetic Factors(e.g., POMC, LEPR, PCSK1) DownstreamActivation FUNCTIONAL

Learn more about the distinct clinical features that distinguish rare genetic disorders of obesity from common obesity and some of the unique symptoms associated with each disorder.2,5,7

  1. Ellacott KL, Cone RD. The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models. Philos Trans R Soc Land B Biol Sci. 2006;361(1471):1265-1274.
  2. Huvenne H, Duberne B, Clément K, Poitou C. Rare genetic forms of obesity: clinical approach and current treatments in 2016. Obes Facts. 2016;9(3):158-173.
  3. Ayers KL, Glicksberg BS, Garfield AS, et al. Melanocortin 4 receptor pathway dysfunction in obesity: patient stratification aimed at MC4R agonist treatment. J Clin Endocrinol Metab. 2018;103(7):2601-2612.
  4. Choquet H, Meyre D. Genetics of obesity: what have we learned? Curr Genomics. 2011;12(3):169-179.
  5. Adan RAH, Hillebrand TJJG, la Fleur SE, Kas MJH, de Krom M. The MC4 receptor and control of appetite. B J Pharmacol. 2006;149(7):815-827.
  6. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Grüters A. Severe early-onset obesity, adrenal insufficiency, and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19(2):155-157.
  7. Styne D, Arslanian S, Connor E, et al. Pediatric obesity—assessment, treatment, and prevention: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2007;102(3);709-757.