黑素皮质素受体4(MC4R)激活基因位于称为下丘脑的脑区,激发饱足或不饿的感受。干扰MC4R激活或发挥功能的变异,与饥饿感持续以及儿童期肥胖有关联。
通过研究一位患有严重肥胖的女孩组织样本,德国莱比锡大学科学家发现了一种特定基因,刺鼠信号蛋白(ASIP)基因,会在正常情况下本不表达该基因的细胞里高水平表达,这些细胞包括脂肪细胞、白细胞和由个体细胞重编程产生的下丘脑样神经元。遗传分析表明,重排将一个ASIP基因拷贝放在了一个启动子旁边——这是驱动基因表达的DNA区域,从而解释了为何该基因在每个组织中持续高水平表达。这一已确认的染色体重排的性质,还意味着大多数常规肥胖的遗传形式检测都不会发现它。ASIP会抑制MC4R的激活,因此在下丘脑细胞中非正常的ASIP表达为肥胖提供了可能的解释。
研究团队随后在超过1700名肥胖儿童的队列中特别搜索这一重排,识别出4名携带者并确认了其中3人的ASIP过表达。这一观察与肥胖遗传小鼠模型一致,这一模型中肥胖是由小鼠版本的ASIP异常表达引起的。但是,直到现在才发现人类中与肥胖有关的涉及ASIP的类似突变。
研究团队认为,在测试队列中基因重排的频率较高,需要在其他患者队列中进行额外的定向筛查。虽然在分离细胞中的这些实验支持他们的模型,但要确定地将基因重排与人类的肥胖相关联,还需要进一步在人类和动物模型中进行研究。
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