Environmental, social, and genetic factors contribute to overeating and reduced physical activity, leading to weight gain. Over time, weight gain is often associated with the development of hypertension, dyslipidemia, and cardiovascular disease. Obesity-related dyslipidemia is characterized by elevated serum triglyceride (TG) levels, elevated low-density lipoprotein (LDL) cholesterol levels, and low high-density lipoprotein (HDL) cholesterol levels. This lipid profile has a pro-atherosclerotic effect. However, the mechanisms by which obesity causes changes in lipid levels remain unclear.
Recently, researchers at the University of Cambridge published a research paper entitled "Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides, and cardiovascular disease risk" in the top international medical journal Nature Medicine.
Obesity is generally associated with elevated LDL cholesterol levels and an increased risk of cardiovascular disease. This study presents a paradoxical finding-people carrying the MC4R gene mutation are severely obese, yet they have lower LDL cholesterol levels and a lower risk of heart disease than their age-matched peers with similar body mass index (BMI).
This research stemmed from a team's attempt to understand the fundamental mechanisms regulating weight and why some obese individuals maintain good heart health. They focused on the MC4R gene, which encodes a key protein in the brain, the melanocortin receptor-4 (MC4R). Activation of MC4R suppresses appetite and reduces food intake. However, a loss-of-function mutation in MC4R leads to overeating and severe obesity. It is estimated that approximately 1% of obese individuals and 5% of obese children carry the MC4R gene mutation.
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The research team analyzed genetic data from participants in two studies: the Genetics of Obesity Study and the UK Biobank, identifying hundreds of individuals carrying the MC4R gene mutation. The team found that in the Genetics of Obesity Study, 144 adults had a loss-of-function MC4R gene mutation. They had lower blood pressure, and lower levels of total cholesterol, LDL cholesterol, and triglycerides than individuals with normal MC4R gene function and similar levels of obesity. In the UK Biobank, individuals carrying at least one copy of the MC4R gene mutation had lower blood lipid levels and a lower risk of heart disease than those with normal MC4R gene function and similar weight.
Figure 1. Model of changes in lipid metabolism seen in people with MC4R deficiency. (Zorn S, et al., 2025)
The research team further discovered that after a high-fat diet, 11 obese individuals with MC4R protein dysfunction processed lipids differently from 15 obese individuals with normal MC4R protein function. The former showed lower increases in triglyceride-rich lipoproteins and metabolomics markers of fatty acid oxidation after a high-fat diet, which favors triglyceride storage in adipose tissue.
Based on these findings, the research team concluded that MC4R in the human brain regulates lipid metabolism and cardiovascular disease risk, providing a basis for developing potential drugs or therapies to reduce cardiovascular disease risk.
Reference
Zorn S, et al. Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk. Nature Medicine, 2025: 1-9.