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.

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

“…In our previous study, we identified several candidate protective factors in Tsn KO mice that may contribute to their ability to retain glucose tolerance [5]. As described previously and as shown in the current study, these mice have a higher proportion of subcutaneous fat, which is thought to protect against glucose intolerance [24].…”

“…Following initial characterization of the Tsnax(E126A) mice, we proceeded to compare the metabolic profiles of male and female mice that are homozygous for the Figure 1C) are decreased to a similar extent in both Tsn KO and Tsnax(E126A) mice. We previously showed that the elevated adiposity displayed by Tsn KO mice reflect increases in both visceral and subcutaneous fat depots, with a small but significant preference for subcutaneous fat [5]. Overall, Tsn KO and Tsnax(E126A) mice show very similar increases in both visceral and subcutaneous fat depots.…”

“…In our previous characterization of the metabolic profile of male Tsn KO mice, we unexpectedly found that they retain glucose tolerance despite their robust adiposity [5].…”

“…The weight of the quadriceps femoris muscle was used as a gauge of muscle mass. Determination of subcutaneous and visceral fat depots was performed as described in Shah et al [5].…”

“…Analysis of mice carrying genetic mutations that elicit abnormalities in adipose tissue has yielded important insights into these processes [4]. Accordingly, we have in recent studies characterized the metabolic profile of Tsn KO mice that display robust adiposity in the context of normal body weight and found that these mice retain normal glucose tolerance [5].…”