Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.
Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency.
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DOI：
10.1016/j.molmet.2017.06.015
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发表时间：
2017-10
影响因子：
8.1
通讯作者：
Van der Ploeg LHT
中科院分区：
文献类型：
--
作者：
Collet TH;Dubern B;Mokrosinski J;Connors H;Keogh JM;Mendes de Oliveira E;Henning E;Poitou-Bernert C;Oppert JM;Tounian P;Marchelli F;Alili R;Le Beyec J;Pépin D;Lacorte JM;Gottesdiener A;Bounds R;Sharma S;Folster C;Henderson B;O'Rahilly S;Stoner E;Gottesdiener K;Panaro BL;Cone RD;Clément K;Farooqi IS;Van der Ploeg LHT
阿黑皮素原（POMC）衍生肽作用于表达黑皮质素4受体（MC 4 R）的神经元以减轻体重。Setmelanotide是一种高效的MC 4 R激动剂，可导致饮食诱导的肥胖动物和POMC完全缺乏的肥胖个体体重减轻。虽然POMC缺乏症非常罕见，但1-5%的严重肥胖个体在MC 4 R中具有杂合突变。我们试图评估塞米拉诺肽在人类MC 4 R缺乏症中的功效。我们在啮齿动物研究和人体临床试验中研究了塞替米拉诺肽对细胞中突变型MC 4 Rs的影响以及对塞替米拉诺肽给药的体重减轻反应。我们注释了369个已发表的MC 4 R变体的功能状态。在细胞中，我们表明，Setmelanotide在MC 4 R上比内源性配体α-黑素细胞刺激激素显着更有效，并且可以通过严重受损的MC 4 R突变体的子集来预防性地拯救信号传导。与MC 4 R杂合缺陷小鼠相比，野生型啮齿动物似乎对Setmelanotide更敏感，而MC 4 R敲除小鼠则没有反应。在一项为期28天的1b期临床试验中，Setmelanotide导致肥胖MC 4 R变异携带者体重减轻。与MC 4 R缺陷患者或肥胖对照相比，具有MC 4 R上游POMC缺陷的患者显示出使用Setmelanotide的显著更多的体重减轻。Setmelanotide导致MC 4 R缺乏的肥胖人群体重减轻;然而，进一步的研究是合理的，以确定Setmelanotide是否可以在MC 4 R缺乏的肥胖人群的子集中引起临床上有意义的体重减轻。
Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1–5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency. We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants. In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls. Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.
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Williams KW
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