Melanocortin-4 receptor pathway overview

The hypothalamus is a key part of the brain that helps regulate hunger; as part of this, the hormone leptin, produced by adipose (fat) tissue, falls in response to fasting. This fall in leptin leads to the brain triggering actions to restore energy balance. The melanocortin-4 receptor (MC4R) pathway is a key part of this process and a critical regulator of hunger and energy balance which helps maintain stable body weight.1

Rare MC4R pathway diseases, which lead to hyperphagia (pathological, insatiable hunger) and early-onset obesity, are distinct from general obesity.1

Rare MC4R pathway diseases generally arise because of the following:
Rare, highly impactful variants in just one gene that result in loss of function in the MC4R pathway
Rare, highly impactful variants in different families of genes that lead to diseases such as Alström syndrome and Bardet-Biedl syndrome
An acquired injury to the hypothalamic region resulting in impairment to the MC4R pathway. This leads to hypothalamic obesity

One of the cardinal symptoms of rare MC4R pathway diseases is hyperphagia. Hyperphagia is characterised by an overwhelming, heightened, and relentless hunger, a longer time to reach satiety, a shorter duration of satiety, and, potentially, extreme food-seeking behaviours such as waking up at night to find food. Hyperphagia leads to excess energy intake, which contributes to obesity.5,6

Obesity results from factors that disrupt the balance of energy intake (food consumption) and energy expenditure (metabolic rate, thermogenesis, and physical activity). While many environmental factors can influence this balance, our genes also significantly define our body weight. Research has shown that some naturally arising genetic variants are associated with obesity.1,6,7

Functional pathway signalling
The MC4R pathway plays a key role in 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.1,2,6
Impaired pathway signalling
In patients with a rare MC4R pathway disease, MC4R pathway signalling is impaired due to genetic variants upstream of the MC4 receptor, leading to hyperphagia and early-onset, severe obesity.8
Learn more
Learn more about the mechanism behind rare MC4R pathway diseases
2 mins
Learn more about the mechanism behind rare MC4R pathway diseases
Play video
Learn more about the mechanism behind rare MC4R pathway diseases
3 mins
Learn more about the cardinal symptoms of rare MC4R pathway diseases
Dr Ashley Shoemaker, Vanderbilt University Medical Center and Dr Ilene Fennoy, New York-Presbyterian Hospital/Columbia University Medical Center explain more about the clinical presentation of the cardinal symptoms of rare MC4R pathway diseases, hyperphagia and early-onset severe obesity. Including key signs, symptoms and cues to look for during a consultation.
Play video


  1. Fonseca ACP, et al., J Diabetes Complications. 2017;31(10):1549-1561
  2. Huvenne H, et al., Obes Facts. 2016; 9(3):158-173
  3. Haqq AM, et al., Lanc Diab & Endo. 2022 ; 10(12) :859-868
  4. Kim JH, Choi JH. Annals of Pediatric End. 2013;(18):161-167
  5. Heymsfield SB, et al. H. Obesity (Silver Spring). 2014
  6. Littleton H., et al., Mol Diagn Ther. 2020;24(6):653-663
  7. Yazdi F, et al. Peer J. 2015;3:e856.
  8. Eneli I, et al. Appl Clin Genet. 2019; 12: 87–93.