Mutant Wars2 gene in spontaneously hypertensive rats impairs brown adipose tissue function and predisposes to visceral obesity.

摘要

Brown adipose tissue (BAT) plays an important role in lipid andglucose metabolism in rodents and possibly also in humans.Identification of genes responsible for BAT function would shedlight on underlying pathophysiological mechanisms of metabolicdisturbances. Recent linkage analysis in the BXH/HXBrecombinant inbred (RI) strains, derived from Brown Norway(BN) and spontaneously hypertensive rats (SHR), identifiedtwo closely linked quantitative trait loci (QTL) associated withglucose oxidation and glucose incorporation into BAT lipidsin the vicinity of Wars2 (tryptophanyl tRNA synthetase 2(mitochondrial)) gene on chromosome 2. The SHR harborsL53F WARS2 protein variant that was associated with reducedangiogenesis and Wars2 thus represents a prominent positionalcandidate gene. In the current study, we validated this candidateas a quantitative trait gene (QTG) using transgenic rescueexperiment. SHR-Wars2 transgenic rats with wild type Wars2gene when compared to SHR, showed more efficientmitochondrial proteosynthesis and increased mitochondrialrespiration, which was associated with increased glucoseoxidation and incorporation into BAT lipids, and with reducedweight of visceral fat. Correlation analyses in RI strains showedthat increased activity of BAT was associated with ameliorationof insulin resistance in muscle and white adipose tissue.In , these results demonstrate important role ofWars2 gene in regulating BAT function and consequently lipidand glucose metabolism.