Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress.
Nrf2 Improves Leptin and Insulin Resistance Provoked by Hypothalamic Oxidative Stress.
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DOI：
10.1016/j.celrep.2017.01.064
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发表时间：
2017-02
期刊：
影响因子：
8.8
通讯作者：
Yoko Yagishita;A. Uruno;T. Fukutomi;Ritsumi Saito;D. Saigusa;J. Pi;A. Fukamizu;F. Sugiyama;
中科院分区：
文献类型：
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作者：
Yoko Yagishita;A. Uruno;T. Fukutomi;Ritsumi Saito;D. Saigusa;J. Pi;A. Fukamizu;F. Sugiyama;
下丘脑功能丧失与糖尿病发病之间的关系仍不清楚。因此，我们产生了一个有针对性的氧化应激小鼠模型，利用条件性敲除（KO）的硒代半胱氨酸-tRNA（Trsp）使用大鼠胰岛素启动子驱动的Cre（RIP-Cre）。这些Trsp-KO（TrspRIPKO）小鼠表现出下丘脑细胞和胰腺β细胞的Trspin缺失，导致下丘脑氧化应激增加和严重的胰岛素抵抗。瘦素信号被抑制，下丘脑中阿黑皮素原阳性神经元的数量减少。相比之下，在胰腺β细胞中特异性表达Cre但在下丘脑中不表达Cre的Trsp-KO小鼠（TrspIns1KO）不显示胰岛素和瘦素抗性，证明下丘脑在糖尿病发作中的关键作用。Nrf2（NF-E2相关因子2）调节抗氧化基因的表达。增加Nrf2信号转导抑制下丘脑氧化应激，并改善TrspRIPKO小鼠的胰岛素和瘦素抵抗。因此，Nrf2具有通过减少下丘脑氧化损伤来预防糖尿病发作的潜力。
The relationship between loss of hypothalamic function and onset of diabetes mellitus remains elusive. Therefore, we generated a targeted oxidative-stress murine model utilizing conditional knockout (KO) of selenocysteine-tRNA (Trsp) using rat-insulin-promoter-driven-Cre (RIP-Cre). TheseTrsp-KO (TrspRIPKO) mice exhibit deletion ofTrspin both hypothalamic cells and pancreatic β cells, leading to increased hypothalamic oxidative stress and severe insulin resistance. Leptin signals are suppressed, and numbers of proopiomelanocortin-positive neurons in the hypothalamus are decreased. In contrast,Trsp-KO mice (TrspIns1KO) expressing Cre specifically in pancreatic β cells, but not in the hypothalamus, do not display insulin and leptin resistance, demonstrating a critical role of the hypothalamus in the onset of diabetes mellitus. Nrf2 (NF-E2-related factor 2) regulates antioxidant gene expression. Increased Nrf2 signaling suppresses hypothalamic oxidative stress and improves insulin and leptin resistance inTrspRIPKOmice. Thus, Nrf2 harbors the potential to prevent the onset of diabetic mellitus by reducing hypothalamic oxidative damage.