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Animal models

Deletion of translin (Tsn) induces robust adiposity and hepatic steatosis without impairing glucose tolerance

Abstract

Objective

Translin knockout (KO) mice display robust adiposity. Recent studies indicate that translin and its partner protein, trax, regulate the microRNA and ATM kinase signaling pathways, both of which have been implicated in regulating metabolism. In the course of characterizing the metabolic profile of these mice, we found that they display normal glucose tolerance despite their elevated adiposity. Accordingly, we investigated why translin KO mice display this paradoxical phenotype.

Methods

To help distinguish between the metabolic effects of increased adiposity and those of translin deletion per se, we compared three groups: (1) wild-type (WT), (2) translin KO mice on a standard chow diet, and (3) adiposity-matched WT mice that were placed on a high-fat diet until they matched translin KO adiposity levels. All groups were scanned to determine their body composition and tested to evaluate their glucose and insulin tolerance. Plasma, hepatic, and adipose tissue samples were collected and used for histological and molecular analyses.

Results

Translin KO mice show normal glucose tolerance whereas adiposity-matched WT mice, placed on a high-fat diet, do not. In addition, translin KO mice display prominent hepatic steatosis that is more severe than that of adiposity-matched WT mice. Unlike adiposity-matched WT mice, translin KO mice display three key features that have been shown to reduce susceptibility to insulin resistance: increased accumulation of subcutaneous fat, increased levels of circulating adiponectin, and decreased Tnfα expression in hepatic and adipose tissue.

Conclusions

The ability of translin KO mice to retain normal glucose tolerance in the face of marked adipose tissue expansion may be due to the three protective factors noted above. Further studies aimed at defining the molecular bases for this combination of protective phenotypes may yield new approaches to limit the adverse metabolic consequences of obesity.

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Acknowledgements

The authors thank Dr. Timothy H. Moran (Johns Hopkins University) for reviewing the manuscript and Dr. Andrew Wolfe for assistance with the indirect calorimetric measurements. We thank Ginny Miller, Zachary Cordner, Seva Khambadkone, and Leonard Marque for their technical assistance. We also thank Conovor Talbot Jr. (the Johns Hopkins Deep Sequencing and Microarray Core Facility) for the microarray analyses, Michele Pucak (the Johns Hopkins Department of Neuroscience Multiphoton Imaging Core), and Nadine Forbes-McBean (the Johns Hopkins Phenotyping Core). Histological procedures were performed by The Johns Hopkins Medical Institutions Reference Histology Laboratory. This work was supported by an NIH/NIDA grant, DA00266 and NINDS grant NS050274.

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APS, MDJ, and XF contributed equally to this work. APS, MDJ, XF, and GJB performed the research. APS, MDJ, XF, GJB, and MS analyzed the data. APS, MDJ, XF, GJB, MJW, KLT, and JMB designed the experiments. APS, MDJ, XF, KLT, and JMB drafted the manuscript. GJB and MJW helped revise the manuscript. APS, MDJ, XF, GJB, and KLT, and JMB are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

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Correspondence to Jay M. Baraban.

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Shah, A.P., Johnson, M.D., Fu, X. et al. Deletion of translin (Tsn) induces robust adiposity and hepatic steatosis without impairing glucose tolerance. Int J Obes 44, 254–266 (2020). https://doi.org/10.1038/s41366-018-0315-7

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