Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk.

IF 50 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Stefanie Zorn, Rebecca Bounds, Alice Williamson, Katherine Lawler, Ruth Hanssen, Julia Keogh, Elana Henning, Miriam Smith, Barbara A Fielding, A Margot Umpleby, Summaira Yasmeen, Maria Marti-Solano, Claudia Langenberg, Martin Wabitsch, Tinh-Hai Collet, I Sadaf Farooqi
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Abstract

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.

MC4R缺乏导致的肥胖与胆固醇、甘油三酯和心血管疾病风险降低有关。
肥胖导致血脂异常,是心血管疾病的主要危险因素。然而,体重增加和脂质代谢的耦合机制尚不清楚。脑黑素皮质素4受体(MC4Rs)调节小鼠的体重和脂质代谢,但这些发现与人类的相关性尚不清楚。在这里,我们调查了由于MC4R缺乏而肥胖的男性和女性的脂质水平。在肥胖遗传学研究队列的7719人中,我们确定了316先证和144名成年家庭成员具有功能缺失(LoF) MC4R突变。在调整肥胖因素后,MC4R缺乏症的成年人的总胆固醇和低密度脂蛋白(LDL)-胆固醇和甘油三酯水平低于英国生物银行(UK Biobank)的336,728名对照组。与非携带者相比,英国生物银行中LoF MC4R变异携带者的血脂水平较低,患心血管疾病的风险较低,在考虑了体重后。高脂肪饮食后,与对照组相比,MC4R缺乏症患者餐后富含甘油三酯的脂蛋白和脂肪酸氧化代谢组学标志物的上升减少,这种变化有利于甘油三酯在脂肪组织中的储存。我们得出结论,中心MC4Rs调节人类脂质代谢和心血管疾病风险,强调了降低心血管风险的潜在治疗方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Nature Medicine
Nature Medicine 医学-生化与分子生物学
CiteScore
100.90
自引率
0.70%
发文量
525
审稿时长
1 months
期刊介绍: Nature Medicine is a monthly journal publishing original peer-reviewed research in all areas of medicine. The publication focuses on originality, timeliness, interdisciplinary interest, and the impact on improving human health. In addition to research articles, Nature Medicine also publishes commissioned content such as News, Reviews, and Perspectives. This content aims to provide context for the latest advances in translational and clinical research, reaching a wide audience of M.D. and Ph.D. readers. All editorial decisions for the journal are made by a team of full-time professional editors. Nature Medicine consider all types of clinical research, including: -Case-reports and small case series -Clinical trials, whether phase 1, 2, 3 or 4 -Observational studies -Meta-analyses -Biomarker studies -Public and global health studies Nature Medicine is also committed to facilitating communication between translational and clinical researchers. As such, we consider “hybrid” studies with preclinical and translational findings reported alongside data from clinical studies.
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