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Although certain genetic mutations of an appetite-regulating receptor in the brain lead to obesity, they also reduce cholesterol levels and risk of cardiovascular disease in those affected. Researchers at Ulm University Hospital have discovered this in an international study, demonstrating for the first time that signalling pathways in the brain directly intervene in the fat metabolism. This could open up new perspectives for the prevention of heart disease. The study results were published in the highly reputable journal "Nature Medicine".
It sounds paradoxical: a genetic mutation that causes severe obesity simultaneously reduces the risk of heart disease and lowers cholesterol levels. But this is exactly what researchers from Ulm University, in collaboration with the Universities of Cambridge and Geneva, were able to show by analysing health data from thousands of people with obesity. This is astonishing because obesity is actually a risk factor for cardiovascular diseases such as heart attacks and strokes - the most common causes of death worldwide. High blood pressure, increased blood lipid levels, insulin resistance and inflammation damage the heart and blood vessels, and reduce the life expectancy of those affected.
The study, which has now been published in "Nature Medicine", focuses on understanding the fundamental mechanisms behind the regulation of body weight - and the question of why some people do not develop heart disease despite having obesity. To answer these questions, the scientists investigated the melanocortin 4 receptor (MC4R), which regulates appetite and thus body weight in the brain. If the MC4R does not function properly due to a rare mutation, it's a cause of genetic obesity. As the analysed data shows, around four percent of children suffering from obesity are affected.
The researchers analysed the genetic sequences of 7719 people with extreme early childhood obesity. They detected changes in MC4R in 316 people and 461 affected family members. The comparison with data from more than 330,000 control subjects without such changes showed that despite a similarly high body mass index, the affected individuals had significantly better blood lipid levels and lower blood pressure. In particular, the values for total cholesterol, the "bad" low-density lipoprotein cholesterol and triglycerides were significantly lower in adults with MC4R changes. The scientists also investigated how the metabolism of people with MC4R defects behaves after a high-fat meal. They found signs that individuals affected by this condition store more fat in their adipose tissue compared to the control group, which could explain the lower fat metabolism values in the blood.
Key role in the regulation of fat metabolism
"Our results suggest that melanocortin-4 receptors in the brain play a key role in the regulation of fat metabolism and can also influence the risk of cardiovascular disease," explains first author Dr Stefanie Zorn from the Division of Paediatric Endocrinology and Diabetology at Ulm University Hospital for Paediatrics and Adolescent Medicine. She analysed the data during a research visit to the Institute of Metabolic Science, Metabolic Research Laboratories in Cambridge. "Obesity is a complex, chronic disease that goes far beyond appearance. Only by better understanding the genetic and underlying biological mechanisms we can develop individual therapies and effectively help those affected," says Professor Martin Wabitsch, Head of the Division of Paediatric Endocrinology and Diabetology at Ulm University Hospital and Deputy Site Director of the German Centre for Child and Adolescent Health (DZKJ) Ulm.
The discoveries made by the international team could have far-reaching consequences for the development of new preventive approaches to cardiovascular diseases. On the one hand, the gained knowledge could be used in prevention by offering targeted genetic tests to people with obesity and low cholesterol levels. On the other hand, the results could also be used for drug research, for example in developing selective MC4R agonists as a part of personalised medicine, which regulate blood pressure without affecting hunger and satiety.
"This study of the world's largest cohort of people with MC4R deficiency provides valuable insights into the complex link between body weight, fat metabolism and cardiovascular health for the first time," says Professor Wabitsch, who is currently also Chairman of the Board of the Centre for Rare Diseases at the University Hospital. He emphasises: "International collaborations such as this are crucial, especially in the case of rare diseases, as they allow for pooling the limited amount of patient data and gain new, comprehensive insights - opening up new perspectives for diagnostics and therapy."
Prof. Dr Martin Wabitsch, Head of the Division of Paediatric Endocrinology and Diabetology at Ulm University Clinic for Paediatrics and Adolescent Medicine, Mail: martin.wabitsch@uniklinik-ulm.de
Dr Stefanie Zorn, research associate in the Division of Paediatric Endocrinology and Diabetology at Ulm University Clinic for Paediatrics and Adolescent Medicine, Mail: stefanie.zorn@uniklinik-ulm.de
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).
DOI: doi.org/10.1038/s41591-025-03976-1
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