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Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk

Stefanie Zorn1,2, Rebecca Bounds1, Alice Williamson3,4

  • 1University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Nature Medicine
|October 16, 2025
PubMed

Insights

Deficiency in brain melanocortin 4 receptors (MC4Rs) lowers cholesterol and triglycerides in humans, reducing cardiovascular disease risk. This suggests MC4Rs are key regulators of lipid metabolism and heart health.

Area of Science:

  • Endocrinology
  • Metabolic Syndrome
  • Cardiovascular Science

Background:

  • Obesity is linked to dyslipidemia and cardiovascular disease, but the underlying mechanisms are unclear.
  • Brain melanocortin 4 receptors (MC4Rs) influence weight and lipid metabolism in animal models, but human relevance is uncertain.
  • Understanding MC4R's role in human lipid metabolism is crucial for cardiovascular disease prevention.

Purpose of the Study:

  • To investigate the impact of melanocortin 4 receptor (MC4R) deficiency on lipid levels and cardiovascular disease risk in humans.
  • To determine if MC4R loss-of-function variants are associated with altered lipid profiles and cardiovascular outcomes.

Main Methods:

  • Analysis of lipid levels in individuals with obesity due to MC4R deficiency (n=460) compared to UK Biobank controls (n=336,728).
  • Assessment of lipid profiles and cardiovascular disease risk in carriers of MC4R loss-of-function variants within the UK Biobank.
  • Evaluation of postprandial lipemia and metabolomic markers after a high-fat meal in individuals with MC4R deficiency versus controls.

Main Results:

  • Adults with MC4R deficiency exhibited lower total cholesterol, LDL-cholesterol, and triglyceride levels compared to controls, independent of adiposity.
  • MC4R variant carriers showed reduced lipid levels and a lower risk of cardiovascular disease, even after adjusting for body weight.
  • Individuals with MC4R deficiency displayed a blunted postprandial triglyceride response and altered fatty acid oxidation markers, favoring fat storage.

Conclusions:

  • Central MC4Rs play a significant role in regulating human lipid metabolism.
  • MC4R deficiency is associated with improved lipid profiles and reduced cardiovascular disease risk.
  • Targeting MC4Rs presents a potential therapeutic strategy for managing dyslipidemia and cardiovascular risk.

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