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

Fu, Xin; Shah, Anshul; Li, Zhi; Li, Mengni; Tamashiro, Kellie L.K.; Baraban, Jay M.

doi:10.1016/j.molmet.2020.101013

Cited by 6 publications

(4 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mice with floxed alleles of Tsn or Tsnax were generated on a C57BL/6 J background using CRISPR/Cas9 technology as described in Fu et al [ 22 ]. The following Cre driver or reporter lines were obtained from JAX labs or MMRRC (Drd1-Cre (EY217); Ai9 #007909; DAT-Cre #006660; Adora2a-Cre #036158; Ubiquitin C-CreERT2 #007001).…”

Section: Methodsmentioning

confidence: 99%

Elevated body fat increases amphetamine accumulation in brain: evidence from genetic and diet-induced forms of adiposity

Shah

Keighron

et al. 2021

Transl Psychiatry

Self Cite

View full text Add to dashboard Cite

Despite the high prevalence of obesity, little is known about its potential impact on the pharmacokinetics of psychotropic drugs. In the course of investigating the role of the microRNA system on neuronal signaling, we found that mice lacking the translin/trax microRNA-degrading enzyme display an exaggerated locomotor response to amphetamine. As these mice display robust adiposity in the context of normal body weight, we checked whether this phenotype might reflect elevated brain levels of amphetamine. To assess this hypothesis, we compared plasma and brain amphetamine levels of wild type and Tsn KO mice. Furthermore, we checked the effect of diet-induced increases in adiposity on plasma and brain amphetamine levels in wild type mice. Brain amphetamine levels were higher in Tsn KO mice than in wild type littermates and correlated with adiposity. Analysis of the effect of diet-induced increases in adiposity in wild type mice on brain amphetamine levels also demonstrated that brain amphetamine levels correlate with adiposity. Increased adiposity displayed by Tsn KO mice or by wild type mice fed a high-fat diet correlates with elevated brain amphetamine levels. As amphetamine and its analogues are widely used to treat attention deficit disorder, which is associated with obesity, further studies are warranted to assess the impact of adiposity on amphetamine levels in these patients.

show abstract

Section: Methodsmentioning

confidence: 99%

Elevated body fat increases amphetamine accumulation in brain: evidence from genetic and diet-induced forms of adiposity

Shah

Keighron

et al. 2021

Transl Psychiatry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Mice with floxed alleles of Tsn or Tsnax were generated on a C57BL/6J background using CRISPR/Cas9 technology as described in Fu et al[25]. The following Cre driver or reporter lines were obtained from JAX labs or MMRRC (Drd1-Cre (EY217); Ai9 #007909; DAT-Cre #006660; Ubiquitin C-CreERT2 #007001).…”

Section: Methodsmentioning

confidence: 99%

Increased amphetamine-induced hyperactivity intranslin (Tsn)KO mice is driven by elevated adiposity

Shah²,

Keighron³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

The translin/trax microRNA-degrading enzyme mediates activity-induced changes in translation that underlie several long-lasting forms of cellular plasticity. As translin and trax are expressed in dopaminergic and striatal neurons, we investigated whether deletion of Tsn blocks amphetamine sensitization, a long-lasting, translation-dependent form of behavioral plasticity.Although we had hypothesized that constitutive Tsn deletion would impair amphetamine sensitization, we found, instead, that it enhances the hyperlocomotion produced by the initial dose of amphetamine. Since these mice display elevated adiposity, which alters pharmacokinetics of many drugs, we measured brain levels of amphetamine in Tsn knockout mice and found that these are elevated. As conditional Tsn deletion in adulthood does not impact adiposity, we monitored the locomotor response to amphetamine following this manipulation. Acute and sensitized responses to amphetamine are not altered in these mice, indicating that the enhanced amphetamine response displayed by constitutive Tsn knockout mice is due to Tsn absence during development.

show abstract

“…In addition, CtBP1 participates in BAT differentiation [21], and TMEM41B is a novel ER-localized regulator of lipid mobilization and lipid droplets [22]. Regarding the down-regulated proteins, as demonstrated in Table 2, many of the top 10 proteins have been shown to participate in lipid metabolism, brown adipogenesis, and various pathological processes, such as coronary heart disease (CHD) and robust adiposity [23][24][25][26][27][28]. This table contains the 145 proteins that displayed more than 1.2-fold up-regulation in Ang II-infused mice in three independent experiments.…”

Section: Identification Of Depsmentioning

confidence: 99%

Comparative Proteomic Analysis of tPVAT during Ang II Infusion

et al. 2021

View full text Add to dashboard Cite

Perivascular adipose tissue (PVAT) homeostasis plays an important role in maintaining vascular function, and PVAT dysfunction may induce several pathophysiological situations. In this study, we investigated the effect and mechanism of the local angiotensin II (Ang II) on PVAT. High-throughput comparative proteomic analysis, based on TMT labeling combined with LC-MS/MS, were performed on an in vivo Ang II infusion mice model to obtain a comprehensive view of the protein ensembles associated with thoracic PVAT (tPVAT) dysfunction induced by Ang II. In total, 5037 proteins were confidently identified, of which 4984 proteins were quantified. Compared with the saline group, 145 proteins were upregulated and 146 proteins were downregulated during Ang II-induced tPVAT pathogenesis. Bioinformatics analyses revealed that the most enriched GO terms were annotated as gene silencing, monosaccharide binding, and extracellular matrix. In addition, some novel proteins, potentially associated with Ang II infusion, were identified, such as acyl-CoA carboxylase α, very long-chain acyl-CoA synthetase (ACSVL), uncoupling protein 1 (UCP1), perilipin, RAS protein-specific guanine nucleotide-releasing factor 2 (RasGRF2), and hypoxia inducible factor 1α (HIF-1α). Ang II could directly participate in the regulation of lipid metabolism, transportation, and adipocyte differentiation by affecting UCP1 and perilipin. Importantly, the key KEGG pathways were involved in fatty acid biosynthesis, FABP3-PPARα/γ, RasGRF2-ERK-HIF-1α, RasGRF2-PKC-HIF-1α, and STAT3-HIF-1α axis. The present study provided the most comprehensive proteome profile of mice tPVAT and some novel insights into Ang II-mediated tPVAT dysfunction and will be helpful for understanding the possible relationship between local RAS activation and PVAT dysfunction.

show abstract

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

Cited by 6 publications

References 38 publications

Elevated body fat increases amphetamine accumulation in brain: evidence from genetic and diet-induced forms of adiposity

Elevated body fat increases amphetamine accumulation in brain: evidence from genetic and diet-induced forms of adiposity

Increased amphetamine-induced hyperactivity intranslin (Tsn)KO mice is driven by elevated adiposity

Comparative Proteomic Analysis of tPVAT during Ang II Infusion

Contact Info

Product

Resources

About