RMI1 deficiency in mice protects from diet and genetic‐induced obesity
RMI1 deficiency in mice protects from diet and genetic‐induced obesity
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DOI：
10.1111/j.1742-4658.2009.07513.x
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发表时间：
2010-02
期刊：
影响因子：
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通讯作者：
Akira Suwa;M. Yoshino;C. Yamazaki;M. Naitou;Rie Fujikawa;S. Matsumoto;Takeshi Kurama;T. Shimokawa;I. Aramori
中科院分区：
文献类型：
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作者：
Akira Suwa;M. Yoshino;C. Yamazaki;M. Naitou;Rie Fujikawa;S. Matsumoto;Takeshi Kurama;T. Shimokawa;I. Aramori
这项研究的目的是发现和表征新的能量稳态相关分子。我们筛选了用可交换基因捕捉法建立的小鼠胚胎干细胞，并检测了靶基因缺失对饮食和遗传性肥胖的影响。突变菌株0283在RecQ介导的基因组不稳定1(RMI1)基因座有一个插入，具有许多显著的特征，使其能够抵抗代谢异常。在突变小鼠中观察到RMI1表达减少，空腹血糖降低，体重减轻(正常饮食)。当喂食高脂肪食物时，突变小鼠对肥胖具有抵抗力，并表现出改善的葡萄糖耐量和腹部脂肪组织质量和食物摄入量的减少。此外，这些突变体还对致死的黄色刺鼠(Ay)基因诱导的肥胖具有抗性。内源性RMI1基因在KK-Ay小鼠的肝脏和脂肪组织中表达上调。RMI1是布鲁姆综合征基因解旋酶复合体的一个组成部分，它维持基因组的完整性并激活细胞周期检查点机制。有趣的是，饮食诱导的E2F8mRNA的表达在突变小鼠中受到抑制，E2F8是一种重要的细胞周期相关分子。这些结果表明，RMI1对能量平衡的调节是通过调节食物摄入量和脂肪组织中E2F8的表达来实现的。综上所述，这些发现表明RMI1是一个调节能量动态平衡的新分子。
The aim of this study is to discover and characterize novel energy homeostasis‐related molecules. We screened stock mouse embryonic stem cells established using the exchangeable gene trap method, and examined the effects of deficiency of the target gene on diet and genetic‐induced obesity. The mutant strain 0283, which has an insertion at the recQ‐mediated genome instability 1 (RMI1) locus, possesses a number of striking features that allow it to resist metabolic abnormalities. Reduced RMI1 expression, lower fasting‐blood glucose and a reduced body weight (normal diet) were observed in the mutant mice. When fed a high‐fat diet, the mutant mice were resistant to obesity, and also showed improved glucose intolerance and reduced abdominal fat tissue mass and food intake. In addition, the mutants were also resistant to obesity induced by the lethal yellow agouti (Ay) gene. Endogenous RMI1 genes were found to be up‐regulated in the liver and adipose tissue of KK‐Ay mice. RMI1 is a component of the Bloom’s syndrome gene helicase complex that maintains genome integrity and activates cell‐cycle checkpoint machinery. Interestingly, diet‐induced expression of E2F8 mRNA, which is an important cell cycle‐related molecule, was suppressed in the mutant mice. These results suggest that the regulation of energy balance by RMI1 is attributable to the regulation of food intake and E2F8 expression in adipose tissue. Taken together, these findings demonstrate that RMI1 is a novel molecule that regulates energy homeostasis.