In the world’s largest cohort of people with MC4R deficiency, we found low lipid levels and protection from cardiovascular disease.

In a paper published in Nature Medicine, we studied people recruited to the Genetics of Obesity Study (GOOS) cohort. We identified over 700 children and adults with mutations in the melanocortin 4 receptor (MC4R) gene which impaired its function, the world’s largest cohort of people with MC4R deficiency. Compared to 300,000 individuals from UK Biobank with a normal MC4R gene, adults in GOOS with MC4R deficiency had unexpectedly lower levels of low-density lipoprotein (LDL)-cholesterol and lower triglyceride levels despite their severe obesity. In a separate analysis, we found that people from UK Biobank who happened to carry MC4R variants also had significantly lower total cholesterol, LDL-cholesterol and triglyceride levels compared to non-carriers. MC4R deficiency was not associated with any CVD measure. In clinical studies, 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 last month’s Nature Medicine, we published another paper on MC4R deficiency. Here we worked with scientists at the pharmaceutical company Lilly Inc. By looking at data from the SUSTAIN-1 trial, we found that Tirzepatide (also known as Mounjaro) causes significant weight loss (19%) in people who were found to have MC4R deficiency. This work provides clear support for using this drug and others like it to treat people with obesity due to MC4R deficiency – an important advance for people with this condition who have often struggled with their weight since childhood.

You can read the paper here.