Magel2-null mice are hyper-responsive to setmelanotide, a melanocortin 4 receptor agonist
Magel2-null mice are hyper-responsive to setmelanotide, a melanocortin 4 receptor agonist
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DOI：
10.1111/bph.13540
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发表时间：
2016-09-01
影响因子：
7.3
通讯作者：
Wevrick, Rachel
中科院分区：
文献类型：
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作者：
Bischof, Jocelyn M.;Van Der Ploeg, Lex H. T.;Wevrick, Rachel
背景和目的：α -和β -黑色素细胞刺激激素（MSH）来源于前opiomelanocortin (POMC)，是黑素皮质素4受体的天然激动剂配体，黑素皮质素4受体是能量稳态的关键调节器。最近的啮齿动物和人类数据表明，MAGEL2基因可能调节POMC神经元的激活，是prder - willi综合征（PWS）代谢症状的重要因素。首先，MAGEL2蛋白截断突变的患者表现出许多PWS的临床特征。其次，magel2缺失小鼠可能无法正常激活MC4受体，因为它们在POMC神经元的激活方面存在缺陷，因此可能无法正常释放POMC衍生的MC4受体激动剂配体a和β - msh。magel2缺失小鼠代表了PWS患者代谢和食欲失衡的一种易处理的动物模型。实验方法我们在magel2缺失小鼠中测试了MC4受体激动剂setmelanotide的剂量滴定，该药物正在开发中，用于治疗罕见的单基因肥胖。我们发现magel2缺失小鼠对setmelanotide的食欲抑制和代谢作用过敏。结论和意义setmelanotide可能是一种有用的激素/神经肽替代疗法，用于PWS和罕见的单基因肥胖，表现为POMC神经元功能受损。
BACKGROUND AND PURPOSEalpha- and beta-melanocyte-stimulating hormones (MSH) are derived from pro-opiomelanocortin (POMC) and are the natural agonist ligands of the melanocortin 4 receptor, a key regulator of energy homeostasis. Recent rodent and human data have implicated the MAGEL2 gene, which may regulate activation of POMC neurons, as a significant contributor to the metabolic symptoms observed in Prader-Willi Syndrome (PWS). Firstly, patients with protein truncating mutations in MAGEL2 exhibit numerous clinical characteristics of PWS. Secondly, Magel2-null mice may not normally activate MC4 receptors, as they are defective in the activation of their POMC neurons and hence may fail to normally release the POMC-derived MC4 receptor agonist ligands a-and beta-MSH. Magel2-null mice represent a tractable animal model for the metabolic and appetitive imbalance seen in patients with PWS.EXPERIMENTAL APPROACHWe tested a dose titration of the MC4 receptor agonist setmelanotide, in development for rare monogenic forms of obesity, in Magel2-null mice.KEY RESULTSWe show that Magel2-null mice are hypersensitive to the appetite suppressing and metabolic effects of setmelanotide.CONCLUSION AND IMPLICATIONSSetmelanotide may be a useful investigational hormone/neuropeptide replacement therapy for PWS and rare monogenic forms of obesity exhibiting impaired function of POMC neurons.