RARE GENETIC DISORDERS OF OBESITY
SEVERAL CAUSED BY IMPAIRMENT IN KEY HUNGER PATHWAY1

Several rare genetic disorders of obesity are caused by genetic variants in a key neurosignaling pathway responsible for regulating hunger (the melanocortin-4-receptor [MC4R] pathway).1,2

THE MC4R PATHWAY PLAYS A KEY ROLE IN HUNGER REGULATION

The MC4R pathway is 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.1-3

In patients with several rare genetic disorders of obesity (e.g., Bardet-Biedl syndrome, Leptin deficiency, Alström deficiency), MC4R pathway signaling is impaired due to genetic variants upstream of the MC4 receptor, leading to insatiable hunger (hyperphagia) and early-onset, severe obesity.4,5

Neuropeptide Signal (MSH) Defect  in Upstream Genetic Factors (e.g., POMC, LEPR, PCSK1) IMPAIRED PATHWAY SIGNALING Downstream Activation Neuropeptide Signal (MSH) Upstream Genetic Factors Downstream Activation NORMAL PATHWAY SIGNALING

Rare genetic disorders of obesity have common symptoms that distinguish them from other, more common forms of obesity.1


  1. 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.
  2. 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.
  3. Adan RA, Tiesjema B, Hillebrand JJ, la Fleur SE, Kas MJ, de Krom M. The MC4 receptor and control of appetite. Br J Pharmacol. 2006;149(7):815-827.
  4. 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.
  5. 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 variants in humans. Nat Genet. 1998;19(2):155-157.
FREE* GENETIC TEST
NOW AVAILABLE