PDF(Pubmed)
Abstract：
About half of the world population carries at least one allele of the Ala92-DIO2, which slows down the activity of the type 2 deiodinase (D2), the enzyme that activates T4 to T3. Carrying the Ala92-DIO2 allele has been associated with increased body mass index and insulin resistance, but this has not been reproduced in all populations. To test if the genetic background affects the impact of this polymorphism, here we studied the genetically distant C57Bl/6J (B6) and FVB/N (FVB) mice carrying the Ala92-Dio2 allele as compared to control mice carrying the Thr92-Dio2 allele. Whereas B6-Ala92-Dio2 and B6-Thr92-Dio2 mice-fed chow or high-fat diet-behaved metabolically similar in studies using indirect calorimetry, glucose- and insulin tolerance tests, and measuring white adipose tissue (WAT) weight and liver steatosis, major differences were observed between FVB-Ala92-Dio2 and FVB-Thr92-Dio2 mice: carrying the Ala92-Dio2 allele (on a chow diet) resulted in hypercholesterolemia, smaller WAT pads, hepatomegaly, steatosis, and transcriptome changes in the interscapular brown adipose tissue (iBAT) typical of ER stress and apoptosis. Acclimatization at thermoneutrality (30 °C) eliminated most of the metabolic phenotype, indicating that impaired adaptive (BAT) thermogenesis can be involved. In conclusion, the metabolic impact of carrying the Ala92-Dio2 allele depends greatly on the genetic background of the mouse, varying from no phenotype in B6 mice to a major phenotype in FVB mice. These results will help the planning of future clinical trials studying the Thr92Ala-DIO2 polymorphism and may explain why some clinical studies performed in different populations across the globe have obtained inconsistent results.
摘要：
大约一半的世界人口携带至少一个Ala92-DIO2等位基因，这会减慢2型脱碘酶（D2）的活性，激活T4到T3的酶。携带Ala92-DIO2等位基因与BMI和胰岛素抵抗增加有关，但这并没有在所有人群中复制。为了测试遗传背景是否影响这种多态性的影响，在这里，我们研究了携带Ala92-Dio2等位基因的C57Bl/6J（B6）和FVB/N（FVB）小鼠与携带Thr92-Dio2等位基因的对照小鼠相比。而B6-Ala92-Dio2和B6-Thr92-Dio2小鼠在使用间接量热法的研究中表现代谢相似，葡萄糖和胰岛素耐量试验，测量白色脂肪组织（WAT）重量和肝脏脂肪变性，在FVB-Ala92-Dio2和FVB-Thr92-Dio2小鼠之间观察到主要差异。携带Ala92-Dio2等位基因（在饮食中）导致高胆固醇血症，较小的WAT垫，肝肿大,脂肪变性,和肩胛骨间棕色脂肪组织（iBAT）中典型的内质网应激和凋亡的转录组变化。热中性（30°C）的适应消除了大部分代谢表型，这表明受损的适应性（BAT）产热可能参与。总之,携带Ala92-Dio2等位基因的代谢影响很大程度上取决于小鼠的遗传背景，从B6小鼠的无表型到FVB小鼠的主要表型。这些结果将有助于规划研究Thr92Ala-DIO2多态性的未来临床试验，并可能解释为什么在全球不同人群中进行的一些临床研究获得了不一致的结果。
