Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice,International Journal of Obesity

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Deoxyguanosine kinase mutation F180S is associated with a lean phenotype in mice
International Journal of Obesity ( IF 4.2 ) Pub Date : 2023-01-28 , DOI: 10.1038/s41366-023-01262-z
Cédric Francis Borreguero ₁ , Stephan Wueest _{2,

3} , Constanze Hantel _{1,

4} , Holger Schneider ₅ , Daniel Konrad _{2,

3} , Felix Beuschlein ₁ , Ariadni Spyroglou ₁

Affiliation

Background

Deoxyguanosine kinase (DGUOK) deficiency is one of the genetic causes of mitochondrial DNA depletion syndrome (MDDS) in humans, leading to the hepatocerebral or the isolated hepatic form of MDDS. Mouse models are helpful tools for the improvement of understanding of the pathophysiology of diseases and offer the opportunity to examine new therapeutic options.

Methods

Herein, we describe the generation and metabolic characterization of a mouse line carrying a homozygous Dguok^F180S/F180S mutation derived from an N-ethyl-N-nitrosourea-mutagenesis screen. Energy expenditure (EE), oxygen consumption (VO₂) and carbon dioxide production (VCO₂) were assessed in metabolic cages. LC-MS/MS was used to quantify plasma adrenal steroids. Plasma insulin and leptin levels were quantified with commercially available assay kits.

Results

Mutant animals displayed significantly lower body weights and reduced inguinal fat pad mass, in comparison to unaffected littermates. Biochemically, they were characterized by significantly lower blood glucose levels, accompanied by significantly lower insulin, total cholesterol, high density lipoprotein and triglyceride levels. They also displayed an almost 2-fold increase in transaminases. Moreover, absolute EE was comparable in mutant and control mice, but EE in mutants was uncoupled from their body weights. Histological examination of inguinal white adipose tissue (WAT) revealed adipocytes with multilocular fat droplets reminiscent of WAT browning. In addition, mRNA and protein expression of Ucp1 was increased. Mutant mice also presented differing mitochondrial DNA content in various tissues and altered metabolic activity in mitochondria, but no further phenotypical or behavioral abnormalities. Preliminary data imply normal survival of Dguok^F180S/F180S mutant animals.

Conclusion

Taken together, DGUOK mutation F180S leads to a lean phenotype, with lower glucose, insulin, and lipid levels rendering this mouse model not only useful for the study of MDDS forms but also for deciphering mechanisms resulting in a lean phenotype.

中文翻译：

脱氧鸟苷激酶突变 F180S 与小鼠的瘦表型有关

背景

脱氧鸟苷激酶 (DGUOK) 缺乏症是人类线粒体 DNA 耗竭综合征 (MDDS) 的遗传原因之一，可导致肝脑型或孤立性肝型 MDDS。小鼠模型是提高对疾病病理生理学理解的有用工具，并提供了检查新治疗方案的机会。

方法

在此，我们描述了携带纯合子Dguok ^F180S/F180S突变的小鼠品系的生成和代谢特征，该突变来自N -乙基 - N -亚硝基脲诱变筛选。在代谢笼中评估了能量消耗 (EE)、耗氧量 (VO ₂ ) 和二氧化碳生成量 (VCO _{2 )。}LC-MS/MS 用于量化血浆肾上腺类固醇。血浆胰岛素和瘦素水平用市售的测定试剂盒进行量化。

结果

与未受影响的同窝动物相比，突变动物的体重显着降低，腹股沟脂肪垫质量减少。在生化方面，它们的特点是血糖水平显着降低，同时胰岛素、总胆固醇、高密度脂蛋白和甘油三酯水平显着降低。他们还表现出转氨酶几乎增加了 2 倍。此外，绝对 EE 在突变体和对照小鼠中具有可比性，但突变体的 EE 与其体重无关。腹股沟白色脂肪组织 (WAT) 的组织学检查显示脂肪细胞具有多房脂肪滴，让人联想到 WAT 褐变。此外，Ucp1的 mRNA 和蛋白表达增加了。突变小鼠还在各种组织中呈现出不同的线粒体 DNA 含量，并改变了线粒体中的代谢活动，但没有进一步的表型或行为异常。初步数据表明Dguok ^F180S/F180S突变动物的正常存活。