Possible involvement of 4-hydroxy-2-nonenal in the pathogenesis of leptin resistance in obesity.
Possible involvement of 4-hydroxy-2-nonenal in the pathogenesis of leptin resistance in obesity.
复制标题
4-羟基-2-壬烯醛可能参与肥胖瘦素抵抗的发病机制。
DOI：
10.1152/ajpcell.00080.2018
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
& Ozawa K.
中科院分区：
文献类型：
--
作者：
Hosoi T.;Kuwamura A.;Thon M.;Tsuchio K.;Abd El-Hafeez A.A.;& Ozawa K.
对抗肥胖激素瘦素的不敏感性已被认为参与肥胖的发病机制。然而，瘦素抵抗发展的病理机制还不清楚。本研究旨在探讨肥胖患者瘦素抵抗的病理机制。在本研究中，我们发现4-羟基-2-壬烯醛（4-HNE），醛，可能参与瘦素抵抗的发展。用4-HNE处理稳定表达Ob-Rb瘦素受体的SH-SY 5 Y-Ob-Rb人神经母细胞瘤细胞系，分析瘦素诱导的信号转导。我们发现，4-HNE剂量和时间依赖性抑制瘦素诱导的信号转导和转录激活因子3（STAT 3）磷酸化，瘦素的主要抗肥胖信号。另一方面，4-HNE不影响广泛的细胞蛋白的酪氨酸磷酸化，这表明抑制作用可能是选择性的瘦素信号。4-HNE诱导真核起始因子2α-CCAAT/增强子结合蛋白同源蛋白臂的内质网应激信号通路，可能参与瘦素抵抗的发病机制。总之，这些结果表明，4-HNE可能部分影响内质网应激诱导的未折叠蛋白反应信号，并可能参与瘦素抵抗的发病机制。
Insensitivity to the antiobesity hormone, leptin, has been suggested to be involved in the pathogenesis of obesity. However, the pathological mechanisms underlying the development of leptin resistance are not well-understood. This study aimed to examine the pathological mechanisms of leptin resistance in obesity. In the present study, we found that 4-hydroxy-2-nonenal (4-HNE), an aldehyde, may be involved in the development of leptin resistance. The SH-SY5Y-Ob-Rb human neuroblastoma cell line, transfected to express the Ob-Rb leptin receptor stably, was treated with 4-HNE, and leptin-induced signal transduction was analyzed. We found that 4-HNE dose- and time-dependently inhibited leptin-induced signal transducer and activator of transcription 3 (STAT3) phosphorylation, a major antiobesity signal of leptin. On the other hand, 4-HNE did not affect tyrosine phosphorylation of broad cellular proteins, suggesting that the inhibitory effect may be selective to leptin signaling. Mechanistically, 4-HNE induced the eukaryotic initiation factor 2α-CCAAT/enhancer-binding protein homologous protein arm of endoplasmic reticulum stress signaling, which may be involved in the pathogenesis of leptin resistance. Overall, these results suggest that 4-HNE may partly affect endoplasmic reticulum stress-induced unfolded protein response signaling and may be involved in the pathogenesis of leptin resistance.
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