Section of Adult and Pediatric Endocrinology, Diabetes & Metabolism, University of Chicago Medical Center, Chicago, IL 60637, USA.
Department of Pharmacology, Biomedical Science Institute, University of São Paulo, São Paulo 05508, Brazil.
Endocrinology. 2024 May 27;165(7). doi: 10.1210/endocr/bqae064.
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.
大约有一半的世界人口携带至少一个 Ala92-DIO2 等位基因，该等位基因可减缓 2 型脱碘酶（D2）的活性，该酶可将 T4 转化为 T3。携带 Ala92-DIO2 等位基因与体重指数增加和胰岛素抵抗有关，但并非所有人群都存在这种情况。为了测试遗传背景是否会影响这种多态性的影响，我们在这里研究了遗传上不同的 C57Bl/6J（B6）和 FVB/N（FVB）小鼠，这些小鼠携带 Ala92-Dio2 等位基因，而对照小鼠携带 Thr92-Dio2 等位基因。尽管 B6-Ala92-Dio2 和 B6-Thr92-Dio2 小鼠在使用间接测热法、葡萄糖和胰岛素耐量试验以及测量白色脂肪组织（WAT）重量和肝脂肪变性的研究中表现出代谢相似，但在 FVB-Ala92-Dio2 和 FVB-Thr92-Dio2 小鼠之间观察到了主要差异：携带 Ala92-Dio2 等位基因（在 chow 饮食中）导致胆固醇升高，WAT 垫较小，肝肿大，脂肪变性以及肩胛间棕色脂肪组织（iBAT）的转录组变化，这些变化是内质网应激和细胞凋亡的典型特征。在恒温（30°C）下适应消除了大多数代谢表型，表明适应性（BAT）产热受损可能涉及其中。总之，携带 Ala92-Dio2 等位基因的代谢影响在很大程度上取决于小鼠的遗传背景，从 B6 小鼠中没有表型到 FVB 小鼠中主要表型的变化。这些结果将有助于规划未来研究 Thr92Ala-DIO2 多态性的临床试验，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得出了不一致的结果。
