활성질소종에 의한 렙틴신호전달의 억제

초록

We evaluated the effects of reactive nitrogen species (RNS) on the leptin-induced stimulation of Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) pathway and on the leptin receptor (LEPR) expression using SH-SY5Y cells, and we attempted to present the evidences for RNS involvement in leptin resistance in vivo by measuring the level of nitrogenous stress in hypothalamus of mice fed with high-fat (HF) or matched control diet for various durations. In experiments using cells, STAT3 leptin signaling was significantly inhibited by RNS donors in a dose-dependent manner. The decrease of STAT3 phosphorylation by RNS was recovered by pretreatment with ascorbic acid. Similarily, mRNA and protein levels of leptin receptor (LEPR-b) were down-regulated by RNS through transcriptional and posttranslational mechanism, respectively. Particularly, LEPR-b protein was abruptly decreased by 30 min treatment with RNS donors. In hypothalamus of mice fed with HF over a month but fed with HF for a week, we observed the increase of nitrite level as compared with matched control mice. This increase could be explained by the decrease of nNOS phosphorylation and caveolin-1 expression and the increase of iNOS expression. In consistent with increase of nitrite level, hypothalamic nitrotyrosine immunoreactivity of HF fed mice was higher than that of control mice. Combined results suggest that inhibition of the leptin-mediated STAT3 activation via LEPR-b nitrosation and/or receptor down-regulation by RNS can be a possible mechanism of leptin resistance.