Objective

Deletion of Translin (Tsn) from mice induces an unusual metabolic profile characterized by robust adiposity, normal body weight and glucose tolerance. Translin (TN) protein and its partner, trax (TX), form the TN/TX microRNA-degrading enzyme. Since the microRNA system plays a prominent role in regulating metabolism, we reasoned that the metabolic profile displayed by Tsn KO mice might reflect dysregulation of microRNA signaling.

Methods

To test this hypothesis, we inserted a mutation, E126A, in Tsnax, the gene encoding TX, that abolishes the microRNA-degrading enzymatic activity of the TN/TX complex. In addition, to help define the cell types that drive the adiposity phenotype, we have also generated mice with floxed alleles of Tsn or Tsnax.

Results

Introduction of the E126A mutation in Tsnax does not impair expression of TN or TX proteins or their co-precipitation. Furthermore, these mice display selective increases in microRNAs that match those induced by Tsn deletion, confirming that this mutation in Tsnax inactivates the microRNA-degrading activity of the TN/TX complex. Mice homozygous for the Tsnax (E126A) mutation display a metabolic profile that closely mimics that of Tsn KO mice.

Selective deletion of Tsn or Tsnax from either adipocytes or hepatocytes, two candidate cell types, does not phenocopy the elevated adiposity displayed by mice with constitutive Tsn deletion or the Tsnax (E126A) mutation. Furthermore, global, conditional deletion of Tsn in adulthood does not elicit increased adiposity.

Conclusion

Taken together, these findings indicate that inactivation of the TN/TX microRNA-degrading enzyme during development is necessary to drive the robust adiposity displayed by Tsn KO mice.

中文翻译：

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Translin / trax microRNA降解酶的遗传失活表型表现为Translin（Tsn）缺失诱导的强壮肥胖。

目的

从小鼠中删除Translin（Tsn）会导致异常的代谢特征，其特征是肥胖旺盛，体重正常和葡萄糖耐量高。Translin（TN）蛋白及其伴侣Trax（TX）构成TN / TX microRNA降解酶。由于microRNA系统在调节代谢中起着重要作用，我们认为Tsn KO小鼠显示的代谢谱可能反映了microRNA信号的失调。

方法

为了验证该假设，我们在Tsnax（编码TX的基因）中插入了一个突变E126A，该突变消除了TN / TX复合物的降解microRNA的酶活性。此外，以帮助确定该驱动肥胖表型的细胞类型，我们也产生了小鼠的两侧装接loxP的等位基因Tsn中或Tsnax。

结果

在Tsnax中引入E126A突变不会损害TN或TX蛋白的表达或它们的共沉淀。此外，这些小鼠在microRNA中表现出选择性的增加，与通过Tsn缺失诱导的微小RNA匹配，从而证实Tsnax中的这种突变会激活TN / TX复合物的microRNA降解活性。对于纯合子小鼠Tsnax（E126A）突变显示代谢分布密切模仿那个的Tsn中KO小鼠。

的选择性缺失Tsn中或Tsnax从任脂肪细胞或肝细胞，两个候选类型的细胞，不表型模拟升高的肥胖与组成型显示由小鼠Tsn中删除或Tsnax（E126A）突变。此外，成年期Tsn的整体，有条件的缺失不会引起肥胖的增加。

结论

综上所述，这些发现表明，在发育过程中TN / TX microRNA降解酶的失活是驱动Tsn KO小鼠表现出强健的肥胖所必需的。