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EDUCATION
What is the melanocortin-4 receptor (MC4R) pathway?
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 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, severe obesity, are therefore distinct from general obesity.1
Rare, highly impactful variants in just one gene that result in loss of function in the MC4R pathway.2
Known as monogenic obesity.
Complex genetic syndromes, where obesity is often accompanied by neurodevelopmental delay or dysmorphic features.3
Known as syndromic obesity.
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
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 the MC4R, triggering a reduction in hunger and concomitant increase in energy expenditure.1,2,6
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