MC4R

HIGH

Melanocortin 4 receptor

Chromosome: 18q21.32

Gene Overview

MC4R encodes the melanocortin 4 receptor, a G protein-coupled receptor in the hypothalamic leptin-melanocortin pathway that regulates energy balance and appetite. MC4R is activated by alpha-MSH (from POMC neurons) and inhibited by AgRP; activation suppresses food intake and increases energy expenditure. Loss-of-function mutations cause severe early-onset obesity; common variants (e.g., rs17782313 near MC4R) associate with BMI and obesity in GWAS. MC4R is expressed in paraventricular and other hypothalamic nuclei. The receptor couples to Gs and activates cAMP; mutations disrupt signaling through varied mechanisms. MC4R agonists are emerging as anti-obesity therapeutics.

Molecular Function

  • melanocortin binding
  • G protein-coupled receptor activity
  • cAMP signaling
  • appetite regulation

Protein class: melanocortin receptor

Regulatory Annotation

Promoter activity: Hypothalamic-enriched transcription factors.

Enhancer associations: Obesity GWAS signals near MC4R influence hypothalamic expression.

eQTL tissues: brain, hypothalamus

Tissue Expression Context

brainTPM range: 2-8GTEx vv8
hypothalamusTPM range: 5-15GTEx vv8

Pathways

Linked Diseases & Exposures

Diseases

Exposures

Mechanistic Hypotheses

MC4R loss or hypofunction disrupts leptin-melanocortin satiety signaling; reduced receptor activity increases food intake and reduces energy expenditure, predisposing to obesity; obesogenic environment amplifies genetic effect.

MC4R knockout mice are obese; setmelanotide (MC4R agonist) effective in POMC/LEPR deficiency.

HIGH

Confidence Rating

Overall evidence confidence for this gene entry: HIGH

References

  1. 1.Butler AA, et al. (2001). Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nature Neuroscience. doi:10.1038/nn0901-867
  2. 2.GTEx Consortium (2020). GTEx Consortium. The GTEx Consortium atlas of genetic regulatory effects across human tissues. Science. doi:10.1126/science.aaz1776
  3. 3.Comuzzie AG, et al. (2012). Genome-wide association study for variants that modulate relationships between childhood obesity and plasma metabolite profiles. International Journal of Obesity. doi:10.1038/ijo.2011.208