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Genetic inactivation of the translin/trax microRNA-degrading enzyme phenocopies the robust adiposity induced by Translin (Tsn) deletion

By Xiuping Fu, Aparna P Shah, Zhi Li, Mengni Li, Kellie L Tamashiro, Jay M. Baraban

Posted 25 Apr 2020
bioRxiv DOI: 10.1101/2020.04.25.060665 (published DOI: 10.1016/j.molmet.2020.101013)

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. ### Competing Interest Statement The authors have declared no competing interest.

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