This gene causes obesity — and shields against heart disease
Summary
Researchers report a surprising paradox: certain rare forms of the MC4R gene, which drive severe obesity by disabling a brain “brake” on hunger, are linked to lower LDL (“bad”) cholesterol and reduced rates of heart disease compared with people who have a similar body‑mass index but no MC4R mutation. The study analysed genetic data from the Genetics of Obesity Study (GOOS) and the UK Biobank and identified hundreds of mutation carriers. Findings were published in Nature Medicine (Zorn et al.).
Key Points
- Loss‑of‑function mutations in MC4R impair a brain pathway that normally suppresses appetite, causing substantial weight gain.
- People with obesity due to these MC4R variants show lower LDL cholesterol than BMI‑matched peers.
- MC4R mutation carriers have reduced rates of coronary heart disease despite higher body weight.
- The analysis pulled data from GOOS and the UK Biobank and identified hundreds of carriers across cohorts.
- About 1% of adults with obesity (and up to ~5% of children with obesity) carry MC4R‑impairing variants; roughly 1 in 300 people in the UK.
- Results point to MC4R‑related pathways as potential targets for cholesterol‑lowering or cardioprotective therapies.
Content summary
MC4R encodes a key brain protein that signals when to stop eating. When that signalling is lost, people tend to gain weight. The new work shows that, paradoxically, carriers of MC4R loss‑of‑function variants have lower LDL cholesterol and fewer heart disease events than non‑carriers with similar BMI. The team combined sequencing and health data from large cohorts to compare metabolic and cardiovascular outcomes between carriers and non‑carriers. The pattern suggests that obesity driven by this genetic route carries a different cardiovascular risk profile than obesity from other causes.
Context and relevance
This finding matters because it challenges the simple assumption that higher BMI always means higher cardiovascular risk — genetics and mechanism of weight gain can alter the risk landscape. For researchers and drug developers, MC4R‑linked biology could reveal new targets for lowering cholesterol or protecting the heart without necessarily affecting weight. Clinically, it highlights the value of genetic stratification when assessing cardiometabolic risk in people with obesity.
Why should I read this?
Short version: it’s a proper brain‑twister. Obesity usually screams higher cholesterol and heart risk — but this gene flips that script. If you care about why some people with obesity stay heart‑healthy, or you’re interested in new drug targets, this saves you the time of digging through the paper yourself.