N Nature Medicine · Oct 16, 2025 Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF)MC4Rmutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoFMC4Rvariants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction. Endocrine system and metabolic diseases Genetic association study Metabolism biology mouse experiments
N Nature Medicine · Aug 26, 2025 Tirzepatide leads to weight reduction in people with obesity due to MC4R deficiency The magnitude of weight reduction in the SURMOUNT-1 trial of the dual GLP-1 and GIP receptor agonist tirzepatide suggests that this treatment may be particularly effective in addressing the treatment needs of people with severe obesity (body mass index >40 kg m−2), some of whom may carry rare penetrant genetic variants. Here we investigated the clinical response of men and women in the SURMOUNT-1 trial who carried pathogenic mutations in the melanocortin 4 receptor (MC4R) gene, the most common genetic cause of obesity. We found that 32 of 2,291 people (1.4%) for whom data were available carried pathogenicMC4Rmutations. At baseline,MC4Rmutation carriers exhibited a higher body mass index compared with noncarriers (40 kg m−2versus 38 kg m−2;P= 0.036). In the treatment arm, the weight loss trajectory over 72 weeks was comparable in both groups: 18.3% weight reduction inMC4Rmutation carriers versus 19.9% in noncarriers. We conclude that tirzepatide is an effective treatment for the most common genetic subtype of obesity, MC4R deficiency. Endocrine system and metabolic diseases Metabolism Metabolism Genetics Human Drug Development Clinical
