背景:腰臀比(WHR)增加与2型糖尿病和心血管疾病的死亡率和风险增加相关。TBX15-WARS2基因座一直与WHR增加相关。先前对低形Wars2V117L/V117L小鼠模型的研究发现,表型包括严重减少的脂肪量,白色脂肪组织(WAT)褐变,表明Wars2可能是脂肪分布和WAT褐变的潜在调节剂。方法:为了测试Wars2V117L/V117L小鼠不同脂肪库的褐变诱导差异,我们测量了一个4个月大的食物喂养队列的皮下和内脏WAT和棕色脂肪组织(BAT)的多个褐变标记.为了解释之前观察到的脂肪量减少,我们还在同一队列中检测了血浆丝裂素FGF21和GDF15的上调以及食物摄入的差异.最后,为了测试与饮食相关的脂肪分布差异,我们将Wars2V117L/V117L小鼠置于低脂或高脂饮食中(LFD,HFD),并通过Echo-MRI评估其身体组成,并比较6个月大时的最终脂肪储库重量。结果:喂食的Wars2V117L/V117L小鼠在皮下腹股沟WAT储库(iWAT)中的WAT褐变标记基因表达变化大于内脏性腺WAT储库(gWAT)。这些小鼠还表现出减少的食物摄入和升高的血浆FGF21和GDF15以及来自心脏和BAT的mRNA。当暴露于HFD时,Wars2V117L/V117L小鼠表现出对饮食诱导的肥胖的抵抗力,并且gWAT:iWAT比值降低了雄性和HFD特异性。结论:Wars2基因功能的严重降低会导致全身表型,从而导致FGF21和GDF15的上调,从而导致食物摄入量减少以及褐变和脂肪量的储库特异性变化。
Background: Increased waist-to-hip ratio (WHR) is associated with increased mortality and risk of type 2 diabetes and cardiovascular disease. The TBX15-
WARS2 locus has consistently been associated with increased WHR. Previous study of the hypomorphic
Wars2 V117L/V117L mouse model found phenotypes including severely reduced fat mass, and white adipose tissue (WAT) browning, suggesting
Wars2 could be a potential modulator of fat distribution and WAT browning. Methods: To test for differences in browning induction across different adipose depots of
Wars2 V117L/V117L mice, we measured multiple browning markers of a 4-month old chow-fed cohort in subcutaneous and visceral WAT and brown adipose tissue (BAT). To explain previously observed fat mass loss, we also tested for the upregulation of plasma mitokines FGF21 and GDF15 and for differences in food intake in the same cohort. Finally, to test for diet-associated differences in fat distribution, we placed
Wars2 V117L/V117L mice on low-fat or high-fat diet (LFD, HFD) and assessed their body composition by Echo-MRI and compared terminal adipose depot weights at 6 months of age. Results: The chow-fed Wars2 V117L/V117L mice showed more changes in WAT browning marker gene expression in the subcutaneous inguinal WAT depot (iWAT) than in the visceral gonadal WAT depot (gWAT). These mice also demonstrated reduced food intake and elevated plasma FGF21 and GDF15, and mRNA from heart and BAT. When exposed to HFD, the Wars2 V117L/V117L mice showed resistance to diet-induced obesity and a male and HFD-specific reduction of gWAT: iWAT ratio. Conclusion: Severe reduction of Wars2 gene function causes a systemic phenotype which leads to upregulation of FGF21 and GDF15, resulting in reduced food intake and depot-specific changes in browning and fat mass.