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首页> 外文期刊>Life sciences >Excessive nitric oxide attenuates leptin-mediated signal transducer and activator of transcription 3 activation.
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Excessive nitric oxide attenuates leptin-mediated signal transducer and activator of transcription 3 activation.

机译：过量的一氧化氮会减弱瘦素介导的信号转导子和转录激活因子3。

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摘要

The mechanisms of leptin resistance observed in most cases of human obesity are poorly understood. Therefore, we evaluated the effects of nitric oxide (NO) on the leptin-induced activation of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathways and on the leptin receptor (LEPR) expression using SH-SY5Y cells. Here, we show that the NO donor spermine/NONOate inhibited leptin-induced activation of STAT3 in vitro. The inhibition of leptin-mediated STAT3 phosphorylation caused by excessive NO was partially prevented by a sulfhydryl reducing agent, ascorbic acid. Cellular experiments show that reduced expression of long form leptin receptor (LEPR-b) and STAT3 protein instability induced by NO may be mechanisms of the NO-mediated inhibition of leptin-STAT3 signaling. We also present data showing that the hypothalamic NO content of high-fat (HF)-diet-induced obese mice was higher than that of control mice; this is likely caused by decreased caveolin-1 expression and increased nNOS expression induced by HF diet over 19 weeks. Concurrently with the overproduction of NO, the decrease of hypothalamic LEPR-b in obese mice also supports these in vitro data. Combined results suggest that excess of NO can induce the attenuation of leptin-mediated STAT3 activation through reduced expression of LEPR-b mRNA and instability of STAT3 protein at least in part. Furthermore, our in vivo data indicate that long-term HF diet induces hypothalamic overproduction of NO, which may be related with leptin insensitivity. However, further study is required to warrant direct in vivo evidence of a causal relationship between endogenous excess of hypothalamic NO and central leptin resistance.
机译：在大多数人类肥胖病例中观察到的瘦素抵抗机制尚不清楚。因此，我们评估了一氧化氮（NO）对瘦素诱导的Janus激酶/信号转导子和转录激活因子3（JAK / STAT3）通路的激活以及瘦素受体（LEPR）表达的影响（使用SH-SY5Y细胞）。在这里，我们显示NO供体精胺/ NONOate在体外抑制瘦素诱导的STAT3激活。巯基还原剂抗坏血酸可部分阻止由过量NO引起的瘦素介导的STAT3磷酸化的抑制。细胞实验表明，长链瘦素受体（LEPR-b）的表达降低和NO诱导的STAT3蛋白不稳定性可能是NO介导的瘦素STAT3信号传导抑制的机制。我们还提供了数据，表明高脂（HF）饮食诱导的肥胖小鼠的下丘脑NO含量高于对照组。这很可能是由HF饮食诱导的19周内小窝蛋白1表达降低和nNOS表达增加所致。与NO的过量产生同时，肥胖小鼠下丘脑LEPR-b的减少也支持了这些体外数据。综合结果表明，过量的NO至少可以部分通过降低LEPR-b mRNA的表达和STAT3蛋白的不稳定性来诱导瘦素介导的STAT3激活的减弱。此外，我们的体内数据表明，长期的高频饮食会诱发下丘脑NO的过度生成，这可能与瘦素不敏感有关。然而，需要进一步的研究以确保在体内直接证明下丘脑NO内源性过量与中央瘦素抵抗之间存在因果关系。

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