Over 1 billion adults are living with obesity1, a condition strongly associated with dyslipidemia and cardiovascular disease (CVD), yet the biological links between weight gain and lipid metabolism remain uncertain. In mice, the brain’s melanocortin-4-receptor (MC4R) regulates appetite and lipid balance, but its role in humans is less clear.
A new study in Nature Medicine2 examined people with obesity due to MC4R deficiency. The researchers found that, unlike more common forms of obesity, this genetic subtype is linked to lower cholesterol, triglycerides, and blood pressure, suggesting that MC4R signaling in the brain plays a direct role in controlling lipid metabolism.
The team sequenced the MC4R gene in 7,719 children with severe early-onset obesity from the Genetics of Obesity Study (GOOS) cohort. They identified 316 probands with pathogenic variants, defined as MC4R changes that impaired receptor trafficking, signaling, binding, or dimerization and co-segregated with obesity in families, representing 4.1% of the group, and confirmed 144 additional adult family members as carriers.
To assess metabolic differences, lipid and blood pressure data from these 144 adult family members were compared with 336,728 adults from the UK Biobank dataset. Analyses were adjusted for body mass index (BMI) to separate the effect of adiposity from that of MC4R function.
Lipid and Blood Pressure Profiles
Adults with MC4R deficiency had lower total cholesterol (TC), LDL-cholesterol (LDL-C), and triglyceride (TG) levels after BMI adjustment. HDL-cholesterol (HDL-C) and blood glucose were unaffected. Systolic and diastolic blood pressures were also lower across BMI categories.
In the UK Biobank dataset, carriers of loss-of-function (LoF) MC4R variants showed similar lipid patterns: lower TC, LDL-C, and TG after adjustment for BMI, compared to non-carriers. However, the authors report that LoF variants were not significantly associated with CVD outcomes, with odds ratios ranging from 0.997 to 1.034.
High-fat Meal Study
To examine lipid handling in real time, the researchers conducted a high-fat meal challenge in 11 adults with MC4R deficiency and 15 matched controls. After eating a 674 kcal meal (60% fat), blood samples were taken every 30 minutes for 6 hours.
People with MC4R deficiency showed a smaller and shorter rise in TG-rich lipoproteins:
These findings suggest faster clearance of TG-rich particles in people with MC4R deficiency, despite similar fasting lipid levels. Metabolic data also indicated reduced fatty-acid oxidation after the meal.
Gain-of-Function Variants
The study also analyzed two gain-of-function (GoF) variants of MC4R (Val103Ile and Ile251Leu) in the UK Biobank. Carriers of these variants had lower BMI, higher HDL-C, and lower TGs and glycated hemoglobin, but showed no difference in LDL-C, blood pressure, or coronary artery disease risk.
The results indicate that the MC4R pathway connects the brain’s regulation of energy balance with lipid metabolism in humans. Individuals with markedly reduced MC4R signalling are typically obese but show a lipid pattern usually associated with lower cardiovascular risk.
This phenotype contrasts with patterns seen in common obesity, where cholesterol, TGs, and blood pressure typically rise together. This contrast suggests that central neural circuits can influence lipid handling independently of body weight. Findings such as these support a growing focus on genetic subtypes of common diseases, where targeted interventions depend on understanding molecular pathways rather than broad clinical categories.
The authors propose two potential mechanisms for their findings, which are yet to be tested:
These hypotheses highlight how central signalling pathways may shape metabolic outcomes through mechanisms distinct from adiposity itself.
This study provides a rare example of a genetically driven obesity that does not produce the expected cardiovascular risk profile. This distinction highlights the heterogeneity of obesity and the importance of genetic context in predicting metabolic outcomes. Cardiometabolic research increasingly relies on human genetic models to identify protective mechanisms that could inform treatment design. MC4R deficiency illustrates how dissecting rare variants can reveal physiological pathways that influence common diseases.
The findings also illustrate how rare variant studies can identify physiological pathways that separate lipid metabolism from body mass. While LoF MC4R variants do not appear to reduce cardiovascular events, the consistent pattern of lower LDL-C and TGs points to new questions about how the brain controls lipid homeostasis.
The authors caution that MC4R deficiency is rare and its lipid profile should not be seen as protective against obesity, but as a model for studying how the brain regulates lipid and energy balance. They also note several limitations: the small sample size for the high-fat meal test, the lack of direct measures of lipoprotein-lipase activity, and potential differences between clinical and population-based cohorts. They emphasize that further work is needed to test the proposed mechanisms linking MC4R, the sympathetic nervous system, and hepatic LDL receptors. A related paper in Nature Medicine reports that the GLP-1 and GIP receptor agonist tirzepatide induces weight loss in individuals with MC4R deficiency, showing that pharmacologic modulation of this pathway remains possible, even when the receptor itself is impaired3.
This study highlights a shift in metabolic research: understanding disease risk through mechanistic biology rather than BMI and biochemical tests alone. These findings expose a gap in public health strategies that treat obesity as a uniform condition, showing that weight alone does not reliably predict metabolic risk. Current prevention frameworks often assume that reducing BMI will automatically improve cardiometabolic health, yet mechanistic studies such as this one suggest that risk depends as much on molecular signalling as on body composition. By showing that lipid regulation can diverge from weight, it points toward a more precise definition of metabolic health.