In 2011, WARS2 was identified within a locus associated with waist-hip-ratio (WHR) in a human GWAS study (1). WHR is a measure of body fat distribution. WARS2 expression was shown to be significantly reduced in both the subcutaneous and visceral adipose tissue of obese humans compared with lean humans (2). WARS2 encodes mitochondrial tryptophanyl tRNA synthetase. Mitochondrial aminoacyl tRNA synthetases (mtRS) are essential to the generation of complexes within the oxidative phosphorylation pathway (OXPHOS). Mutations within several mtRSs encoding genes can cause a range of mitochondrial disorders in humans with highly variable clinical presentations (3). However there is an unexplained relationship between the disease affected tissue and the affected mtRS. To date, no patient with mitochondrial disease has been documented with a WARS2 mutation. Here I briefly describe a novel mouse model ‘oboe’ which provides a useful vehicle to investigate the tissue specific relationship between WARS2 and adipose tissue. oboe was identified from ‘The Harwell Ageing Screen’ as having significantly reduced total body mass. Affected oboe mice are significantly lighter than littermates from 7 months of age. Body composition analysis at 15 months indicated that the reduction in body mass is representative of significantly reduced fat mass. Affected oboe mice had a mean total fat mass of 5.7g compared with 21.2g in control mice. SNP analysis mapped the lean phenotype to a 73Mb region of chromosome 3 within which a novel ENU-induced mutation in Wars2 was identified. The ENU-induced mutation encodes an amino acid change and induces a novel mis-splicing event where there is complete excision of exon 3. RT-PCR analysis showed that there is less than 40% full-length Wars2 mRNA in Wars2oboe/oboe mouse embryonic fibroblasts (MEFs) compared to Wars2+/+ MEFs. Mitochondrial OXPHOS function was characterized and unexpectedly both basal oxygen consumption and maximal respiratory capacity were significantly increased in Wars2oboe/oboe MEFs compared to Wars2+/+ MEFs. Total mitochondrial mass was also approximately 40% increased in Wars2oboe/oboe MEFs. The relative expression of Pgc-1α, the ‘master regulator’ of mitochondrial biogenesis was over 70% increased in Wars2oboe/oboe MEFs compared with Wars2+/+ MEFs.We hypothesise that the reduction in full-length Wars2 transcript in oboe mice inhibits mitochondrial translation and by extension OXPHOS function. This reduced OXPHOS function triggers a compensatory mechanism through activation of the cellular energy censor AMPK to inhibit anabolic and up-regulate catabolic pathways including: mitochondrial biogenesis, glycolysis, and fatty acid oxidation. Increased catabolic metabolism may explain the lean phenotype observed in oboe mice. The overall aim of this ongoing project is to investigate whether the Wars2oboe ENU-induced mutation has an adipose tissue specific effect.