Gene defect linked to obesity may also protect against heart disease, study finds
A genetic mutation that causes severe obesity may paradoxically protect against heart disease, according to new research published in Nature Medicine.
Scientists have discovered that adults with a deficiency in the melanocortin 4 receptor (MC4R) gene, a well-known cause of inherited obesity, show lower levels of cholesterol and triglycerides and a reduced risk of cardiovascular disease.
The findings challenge long-held assumptions that obesity and heart disease are inseparable, suggesting that genetic factors can alter this relationship.
Researchers from the Genetics of Obesity Study (GOOS) examined the genetic profiles of 7,719 children, identifying 316 probands, the first affected family members and 144 adult relatives carrying MC4R loss-of-function mutations. Despite severe obesity, these individuals had healthier blood pressure and cardiovascular profiles than 336,728 adults from the UK Biobank who served as controls. Even after adjusting for body weight, the protective effects persisted.
Obesity, which affects roughly one in eight people, is usually associated with hypertension and dyslipidaemia, an imbalance of blood lipids marked by high levels of low-density lipoproteins (LDL) and triglycerides and low levels of high-density lipoproteins (HDL). These conditions typically increase the risk of heart disease.
However, the study found that the MC4R receptor, located in the brain, plays a crucial role in regulating how the body processes fat. To explore this, researchers conducted three complementary studies: a clinical analysis of individuals with MC4R variants, a replication using UK Biobank data, and a controlled feeding experiment to assess fat metabolism.
In the final experiment, 11 people with MC4R deficiency were compared with 15 matched volunteers of similar age, sex, and body mass index. After consuming a high-fat meal, those with the mutation showed healthier lipid responses and lower cholesterol levels than the control group.
The results suggest that MC4R deficiency may promote a “metabolically healthy” form of obesity, providing cardiovascular benefits despite excess weight.
Researchers say these insights could pave the way for new heart-protective therapies.
“Drugs that mimic the protective effects of MC4R deficiency on lipid metabolism might reduce cardiovascular risk across the population, independent of weight loss,” the authors wrote.