Increased E4 Activity in Mice Leads to Ubiquitin-containing Aggregates and Degeneration of Hypothalamic Neurons Resulting in Obesity
Increased E4 Activity in Mice Leads to Ubiquitin-containing Aggregates and Degeneration of Hypothalamic Neurons Resulting in Obesity
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DOI：
10.1074/jbc.m110.105841
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发表时间：
2010-05-14
影响因子：
4.8
通讯作者：
Nakayama, Keiichi I.
中科院分区：
文献类型：
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作者：
Susaki, Etsuo;Kaneko-Oshikawa, Chie;Nakayama, Keiichi I.
肥胖已成为一个严重的世界性公共卫生问题。虽然特定大脑区域的神经退化已被认为是人类肥胖表型的原因之一，但这两种情况之间的因果关系尚未得到实验证明。我们现在表明E4B（也称为UFD2a），一种哺乳动物泛素链延伸因子（E4），当在培养细胞或大脑中过度表达时，诱导形成泛素和接头蛋白p62阳性的细胞内聚集体。转基因E4B的小鼠表现出与聚集体形成相关的神经变性，并且在调节食物摄入和能量消耗的下丘脑神经元亚群中表现出特异性的功能损伤，导致暴饮暴食性肥胖和相关代谢异常的发展。E4B转基因小鼠的神经病理与细胞内泛素阳性沉积物形成相关的人类神经退行性疾病相似，表明此类疾病与肥胖及相关代谢紊乱之间存在联系。因此，我们的研究结果为下丘脑神经变性在肥胖中的作用提供了实验证据，并且E4B转基因小鼠应该被证明是研究神经退行性疾病与肥胖关系的有用动物模型。
Obesity has become a serious worldwide public health problem. Although neural degeneration in specific brain regions has been suggested to contribute to obesity phenotype in humans, a causal relationship between these two conditions has not been demonstrated experimentally. We now show that E4B (also known as UFD2a), a mammalian ubiquitin chain elongation factor (E4), induces the formation of intracellular aggregates positive for ubiquitin and the adaptor protein p62 when overexpressed in cultured cells or the brain. Mice transgenic for E4B manifested neural degeneration in association with aggregate formation, and they exhibited functional impairment specifically in a subset of hypothalamic neurons that regulate food intake and energy expenditure, resulting in development of hyperphagic obesity and related metabolic abnormalities. The neural pathology of E4B transgenic mice was similar to that of human neurodegenerative diseases associated with the formation of intracellular ubiquitin-positive deposits, indicating the existence of a link between such diseases and obesity and related metabolic disorders. Our findings thus provide experimental evidence for a role of hypothalamic neurodegeneration in obesity, and the E4B transgenic mouse should prove to be a useful animal model for studies of the relationship between neurodegenerative diseases and obesity.