Mutant Wars2 Gene in Spontaneously Hypertensive Rats Impairs Brown Adipose Tissue Function and Predisposes to Visceral Obesity

Pravenec, Michal; Zidek, Vaclav; Landa, V.; Mlejnek, Petr; Šilhavý, Jan; Šimáková, Miroslava; Trnovská, Jaroslava; Škop, Vojtěch; Marková, Irena; Malínská, Hana; Hüttl, Martina; Kazdová, Ludmila; Bardová, Kristina; Tauchmannová, Kateřina; Vrbacký, Marek; Nůsková, Hana; Mráček, Tomáš; Kopecký, Jan; Houštěk, J

doi:10.33549/physiolres.933811

Cited by 19 publications

(15 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These single-nucleotide polymorphisms (SNPs) are associated with the waist-hip ratio in human genome-wide association studies, which are explained by changes in adipose tissue distribution ( Heid et al., 2010 ). Our studies support the possibility that WARS2 is one of the effector genes in this association locus ( Pravenec et al., 2017 ).…”

Section: Discussionsupporting

confidence: 86%

“…Genetic mapping in the rat for coronary flow and capillary density traits in the heart identified a causal missense variant in Wars2 that reduced WARS2 activity by ∼40% ( Wang et al., 2016 ). It was also shown that the mutation reduced endothelial cell proliferation and activated pro-apoptotic pathways, as well as impairing BAT function ( Pravenec et al., 2017 , Wang et al., 2016 ). Finally, Wang et al.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Wars2 Mutant Mouse Model Displays OXPHOS Deficiencies and Activation of Tissue-Specific Stress Response Pathways

et al. 2018

View full text Add to dashboard Cite

SummaryMutations in genes essential for mitochondrial function have pleiotropic effects. The mechanisms underlying these traits yield insights into metabolic homeostasis and potential therapies. Here we report the characterization of a mouse model harboring a mutation in the tryptophanyl-tRNA synthetase 2 (Wars2) gene, encoding the mitochondrial-localized WARS2 protein. This hypomorphic allele causes progressive tissue-specific pathologies, including hearing loss, reduced adiposity, adipose tissue dysfunction, and hypertrophic cardiomyopathy. We demonstrate the tissue heterogeneity arises as a result of variable activation of the integrated stress response (ISR) pathway and the ability of certain tissues to respond to impaired mitochondrial translation. Many of the systemic metabolic effects are likely mediated through elevated fibroblast growth factor 21 (FGF21) following activation of the ISR in certain tissues. These findings demonstrate the potential pleiotropy associated with Wars2 mutations in patients.

show abstract

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

A Wars2 Mutant Mouse Model Displays OXPHOS Deficiencies and Activation of Tissue-Specific Stress Response Pathways

et al. 2018

View full text Add to dashboard Cite

show abstract

“…WARS2 encodes a mitochondrial tryptophanyl tRNA synthetase that has been linked to mitochondrial-related neurodegeneration [ 30 ]. One study suggested that increased WARS2 expression is associated with decreasing visceral adiposity through effects on brown adipose tissue function [ 31 ]. It is unclear which of the many obesity-associated SNPs in the TBX15/WARS2 region or eBMD-detected SNPs at the TBX15 locus are biologically relevant to obesity or osteoporosis.…”

Section: Introductionmentioning

confidence: 99%

Osteoporosis- and obesity-risk interrelationships: an epigenetic analysis of GWAS-derived SNPs at the developmental gene TBX15

Zhang

Ehrlich

et al. 2020

Epigenetics

View full text Add to dashboard Cite

A major challenge in translating findings from genome-wide association studies (GWAS) to biological mechanisms is pinpointing functional variants because only a very small percentage of variants associated with a given trait actually impact the trait. We used an extensive epigenetics, transcriptomics, and genetics analysis of the TBX15/WARS2 neighbourhood to prioritize this region’s best-candidate causal variants for the genetic risk of osteoporosis (estimated bone density, eBMD) and obesity (waist-hip ratio or waist circumference adjusted for body mass index). TBX15 encodes a transcription factor that is important in bone development and adipose biology. Manual curation of 692 GWAS-derived variants gave eight strong candidates for causal SNPs that modulate TBX15 transcription in subcutaneous adipose tissue (SAT) or osteoblasts, which highly and specifically express this gene. None of these SNPs were prioritized by Bayesian fine-mapping. The eight regulatory causal SNPs were in enhancer or promoter chromatin seen preferentially in SAT or osteoblasts at TBX15 intron-1 or upstream. They overlap strongly predicted, allele-specific transcription factor binding sites. Our analysis suggests that these SNPs act independently of two missense SNPs in TBX15 . Remarkably, five of the regulatory SNPs were associated with eBMD and obesity and had the same trait-increasing allele for both. We found that WARS2 obesity-related SNPs can be ascribed to high linkage disequilibrium with TBX15 intron-1 SNPs. Our findings from GWAS index, proxy, and imputed SNPs suggest that a few SNPs, including three in a 0.7-kb cluster, act as causal regulatory variants to fine-tune TBX15 expression and, thereby, affect both obesity and osteoporosis risk.

show abstract

“…In addition to these advanced QTL mapping strategies developed in rats, RI and HS strains have also contributed to quantitative genetic studies. These rat strains have been used to detect QTLs [48][49][50][51][52][53][54][55][56][57][58][59][60][61] for 1) cardiovascular conditions, such as blood pressure, electrocardiographic parameters, basal mean arterial pressure (MAP), delta MAP and delta heart rate, left ventricular hypertrophy and heart size; 2) metabolic complexity, such as alcohol consumption and propensity for alcohol-induced organ damage, glucose oxidation and its incorporation into brown adipose tissue lipids, insulin resistance, dyslipidemia and glucose handling; 3) behavioral traits, such as shuttle box, automated novel cage activity and elevated zero maze, startle motor response and habituation, anxiety and locomotion traits associated with elevated plus maze, and conditioned taste aversion; 4) physiologic and hormonal quantitative traits, such as serum adiponectin and thyroid stimulating hormone activity, dopamine betahydroxylase enzyme activity, catecholamine biosynthesis and catecholamine secretion; 5) bone fragility, bone mineral density, bone structure and bone strength; 6) hematology, such as full blood count; 7) immunology, such as FACScan analysis of white blood cells; 8) neuroinflammation, such as myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalomyelitis and TNF alpha in serum; and 9) tissue weight, such as adrenal glands, bone, blood, brain, ears, heart, kidney, liver, spinal cord, spleen, and thymus. In addition, Szpirer [62] recently reviewed the use of rats for knockout investigations of QTLs and gene functions.…”

Section: Genome Variationmentioning

confidence: 99%

Genome-to-phenome research in rats: progress and perspectives

et al. 2021

View full text Add to dashboard Cite

Because of their relatively short lifespan (<4 years), rats have become the second most used model organism to study health and diseases in humans who may live for up to 120 years. First-, second- and third-generation sequencing technologies and platforms have produced increasingly greater sequencing depth and accurate reads, leading to significant advancements in the rat genome assembly during the last 20 years. In fact, whole genome sequencing (WGS) of 47 strains have been completed. This has led to the discovery of genome variants in rats, which have been widely used to detect quantitative trait loci underlying complex phenotypes based on gene, haplotype, and sweep association analyses. DNA variants can also reveal strain, chromosome and gene functional evolutions. In parallel, phenome programs have advanced significantly in rats during the last 15 years and more than 10 databases host genome and/or phenome information. In order to discover the bridges between genome and phenome, systems genetics and integrative genomics approaches have been developed. On the other hand, multiple level information transfers from genome to phenome are executed by differential usage of alternative transcriptional start (ATS) and polyadenylation (APA) sites per gene. We used our own experiments to demonstrate how alternative transcriptome analysis can lead to enrichment of phenome-related causal pathways in rats. Development of advanced genome-to-phenome assays will certainly enhance rats as models for human biomedical research.

show abstract

Mutant Wars2 Gene in Spontaneously Hypertensive Rats Impairs Brown Adipose Tissue Function and Predisposes to Visceral Obesity

Cited by 19 publications

References 18 publications

A Wars2 Mutant Mouse Model Displays OXPHOS Deficiencies and Activation of Tissue-Specific Stress Response Pathways

A Wars2 Mutant Mouse Model Displays OXPHOS Deficiencies and Activation of Tissue-Specific Stress Response Pathways

Osteoporosis- and obesity-risk interrelationships: an epigenetic analysis of GWAS-derived SNPs at the developmental gene TBX15

Genome-to-phenome research in rats: progress and perspectives

Contact Info

Product

Resources

About