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) MC4R mutations. 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 LoF MC4R variants 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.
Authors
- A. Margot Umpleby (ORCID: https://orcid.org/0000-0001-6147-7919)
- I. Sadaf Farooqi (ORCID: https://orcid.org/0000-0001-7609-3504)
- Katherine Lawler (ORCID: https://orcid.org/0000-0003-4188-1804)
- Rebecca Bounds (ORCID: https://orcid.org/0000-0001-8830-9456)
- Miriam Smith
- Summaira Yasmeen (ORCID: https://orcid.org/0000-0001-5470-2081)
- Maria Martí-Solano (ORCID: https://orcid.org/0000-0003-0373-8927)
- Stefanie Zorn (ORCID: https://orcid.org/0000-0001-9375-4845)
- Claudia Langenberg (ORCID: https://orcid.org/0000-0002-5017-7344)
- Alice Williamson (ORCID: https://orcid.org/0000-0002-7599-9301)
- Tinh‐Hai Collet (ORCID: https://orcid.org/0000-0002-3243-1222)
- Elana Henning (ORCID: https://orcid.org/0000-0001-9463-794X)
- Julia M. Keogh (ORCID: https://orcid.org/0000-0002-0399-4114)
- Ruth Hanßen (ORCID: https://orcid.org/0000-0002-7283-9302)
- Martin Wabitsch (ORCID: https://orcid.org/0000-0001-6795-8430)
- Barbara A. Fielding
Institutions
- University of Geneva (CH)
- Queen Mary University of London (GB)
- Universität Ulm (DE)
- University of Cambridge (GB)
- University of Surrey (GB)
- University Hospital of Geneva (CH)
- Max Planck Institute for Metabolism Research (DE)
- Wellcome/MRC Institute of Metabolic Science (GB)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- University Hospital Cologne (DE)
- Geneva College (US)
Publication Details
- Journal
- Nature Medicine
- Published
- 2025-10-16
- DOI
- https://doi.org/10.1038/s41591-025-03976-1
- Citations
- 4
- Primary Topic
- Regulation of Appetite and Obesity
- Type
- article
- Field-Weighted Citation Impact
- 3.66
Funders
- National Science Foundation
- National Institute for Health and Care Research
- Deutsche Forschungsgemeinschaft
- Fondation Leducq
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Fondation Leenaards
- Universität zu Köln
- Schweizerischen Gesellschaft für Endokrinologie und Diabetologie