Human MC4R deficiency is associated with low lipid levels and reduced cardiovascular risk.

Commonly, obesity is associated with higher levels of low-density lipoprotein (LDL)-cholesterol and triglycerides and low levels of high-density lipoprotein (HDL)-cholesterol, factors which increase cardiovascular disease (CVD) risk. However, the mechanisms which link obesity to changes in lipid levels are poorly understood.

In a paper published in Nature Medicine, the Farooqi team investigated the role of brain-expressed melanocortin 4 receptors (MC4Rs) in human lipid metabolism by studying the world’s largest cohort of people with loss of function (LOF) mutations in the gene encoding MC4R. Unexpectedly, they found that despite their severe obesity, adults with MC4R deficiency had lower total cholesterol, LDL-cholesterol and triglycerides when compared to 300,000 people of the same age and BMI from UK Biobank who had a normal MC4R gene. In a separate analysis, the team found that people from UK Biobank who happened to carry LOF MC4R variants also had significantly lower total cholesterol, LDL-cholesterol and triglyceride levels compared to non-carriers and MC4R deficiency was not associated with any CVD measure. After a high fat meal, the rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in MC4R deficient people compared to control individuals. These changes favour triglyceride storage in adipose tissue. Cumulatively, these studies demonstrate that brain MC4R signaling regulates human lipid metabolism. Further studies of the mechanisms which mediate the beneficial effects of MC4R inhibition on lipid metabolism may provide new therapeutic targets for obesity associated dyslipidaemia and cardiovascular disease.

In a companion paper in Nature Medicine, the team worked with scientists at the pharmaceutical company Lilly Inc. By looking at data from the SUSTAIN-1 trial, they found that Tirzepatide (also known as Mounjaro) causes significant weight loss (19%) in people with MC4R deficiency. This work provides clear support for using this drug in the treatment of people with obesity due to MC4R deficiency, many of whom have often struggled with weight problems since childhood.

References:

Paper 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

Paper 2 - Bhatnagar, P., Ahmad, N.N., Li, X. et al. Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency. Nat Med (2025). https://doi.org/10.1038/s41591-025-03913-2