Obesity is a primary risk factor for dyslipidaemia and cardiovascular disease (CVD), but the mechanisms linking weight gain to lipid metabolism are not fully understood. A new study suggests that in a specific genetic form of obesity caused by melanocortin 4 receptor (MC4R) deficiency, individuals may have a more favourable cardiometabolic profile despite their higher body weight.¹

This multi-part study investigated lipid levels in individuals with obesity due to MC4R deficiency. Researchers first analysed data from the Genetics of Obesity Study (GOOS) cohort, identifying 316 probands and 144 adult family members with pathogenic loss-of-function (LoF) MC4R mutations. Their cardiometabolic data were compared with 336,728 controls from the UK Biobank.¹

To validate these findings, a gene burden analysis was conducted on MC4R variant carriers within the UK Biobank. Finally, a clinical study examined the postprandial response to a high-fat meal (674 kcal; 60% fat) in 11 individuals with MC4R deficiency and 15 age-, sex-, and BMI-matched controls over a 6-hour period.¹

After adjusting for adiposity, adults with MC4R deficiency in the GOOS cohort had significantly lower levels of total cholesterol, low-density lipoprotein (LDL)-cholesterol, and triglycerides compared to the UK Biobank controls. These findings were replicated in the UK Biobank population, where carriers of LoF MC4R variants also showed a lower risk of CVD compared to noncarriers after accounting for body weight.¹

In the high-fat meal challenge, the postprandial increase in triglyceride-rich lipoproteins (TRLs) was significantly reduced in the MC4R deficiency group. The area under the curve for the postprandial triglyceride response was 92 ± 49 mmol l⁻¹ min⁻¹ in those with MC4R deficiency versus 156 ± 90 mmol l⁻¹ min⁻¹ in controls (p=0.049). Furthermore, the peak postprandial concentration of triglycerides in the TRL fraction was 50% lower in the MC4R deficiency group (0.49 ± 0.14 mmol l⁻¹ vs 0.85 ± 0.39 mmol l⁻¹, p=0.03). Metabolomic analysis also suggested that fatty acid oxidation was impaired.¹

These findings demonstrate that obesity resulting from MC4R deficiency, the most common monogenic form of obesity, is associated with a paradoxical cardiovascular profile, including lower atherogenic lipid levels and reduced blood pressure.² This suggests that the central MC4R pathway plays a distinct role in regulating lipid metabolism, independent of its effects on body weight. "We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction," the authors stated.¹

The researchers suggest that further studies using isotopic tracers are needed to better quantify chylomicron and very-low-density lipoprotein production and clearance rates in humans to fully understand the underlying mechanisms.

This study was funded by Wellcome, Botnar Fondation, the Leducq Foundation, the Bernard Wolfe Health Neuroscience Endowment, NIHR, the Swiss National Science Foundation, and others.

References

1. Zorn S, Bounds R, Williamson A, et al. Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk. Nat Med 2025. https://doi.org/10.1038/s41591-025-03976-1

2. Farooqi IS, Keogh JM, Yeo GSH, et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med 2003;348:1085–1095. https://doi.org/10.1056/NEJMoa022050

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