Down-regulation of Leptin Signaling; Role of Nitric Oxide in Leptin Resistance

초록

The mechanisms of leptin resistance observed in the most cases of human obesity are poorly understood. Recent several reports suggested that the feedback inhibition of leptin signaling and/or the defect in central leptin transport are plausible mechanisms of leptin resistance. However, despite of numerous evidences for the involvement of nitric oxide (NO) in food intake and obesity, the roles of NO in the development of the leptin resistance are not examined. We evaluated the effects of NO on the development of leptin resistance using human neuroblastoma cells. We observed that pretreatment with NO donor abruptly caused a dose-dependent inhibition of leptin-mediated STAT3 phosphorylation in vitro. In addition, the protein expression of long form of the functional leptin receptor (LEPR-b) was down-regulated by treatment with NO in a dose-dependent manner. In vivo experiment, we observed that high-fat diet feeding for various durations (1~19 weeks) induced systemic inflammation and nitrogenous stress in hypothalamus of mice, which was evident by increase of plasma NOx and hypothalamic nitrated protein in obese mice. Combined our results, inhibition of the leptin-induced STAT3 signaling by NO and/or peroxynitrite may be an important mechanism in development of leptin resistance