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内质网应激诱导瘦素抵抗。

Endoplasmic reticulum stress induces leptin resistance.

作者信息

Hosoi Toru, Sasaki Miyako, Miyahara Tsuyoshi, Hashimoto Chie, Matsuo Suguru, Yoshii Michiko, Ozawa Koichiro

机构信息

Department of Pharmacotherapy, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.

出版信息

Mol Pharmacol. 2008 Dec;74(6):1610-9. doi: 10.1124/mol.108.050070. Epub 2008 Aug 28.

Abstract

Leptin is an important circulating signal for inhibiting food intake and body weight gain. In recent years, "leptin resistance" has been considered to be one of the main causes of obesity. However, the detailed mechanisms of leptin resistance are poorly understood. Increasing evidence has suggested that stress signals, which impair endoplasmic reticulum (ER) function, lead to an accumulation of unfolded proteins, which results in ER stress. In the present study, we hypothesized that ER stress is involved in leptin resistance. Tunicamycin, thapsigargin, or brefeldin A was used to induce ER stress. The activation status of leptin signals was measured by Western blotting analysis using a phospho-(Tyr705) signal transducer and activator of transcription 3 (STAT3) antibody. We observed that ER stress markedly inhibited leptin-induced STAT3 phosphorylation. In contrast, ER stress did not affect leptin-induced c-Jun NH(2)-terminal kinase activation. These results suggest that ER stress induces leptin resistance. ER stress-induced leptin resistance was mediated through protein tyrosine phosphatase 1B but not through suppressors of cytokine signaling 3. It is noteworthy that a chemical chaperone, which could improve the protein-folding capacity, reversed ER stress-induced leptin resistance. Moreover, homocysteine, which induces ER stress, caused leptin resistance both in vitro and in vivo. Together, these findings suggest that the pathological mechanism of leptin resistance is derived from ER stress.

摘要

瘦素是一种抑制食物摄入和体重增加的重要循环信号。近年来,“瘦素抵抗”被认为是肥胖的主要原因之一。然而,瘦素抵抗的详细机制尚不清楚。越来越多的证据表明,损害内质网(ER)功能的应激信号会导致未折叠蛋白的积累,从而引发内质网应激。在本研究中,我们假设内质网应激与瘦素抵抗有关。使用衣霉素、毒胡萝卜素或布雷菲德菌素A诱导内质网应激。通过使用磷酸化(Tyr705)信号转导和转录激活因子3(STAT3)抗体的蛋白质印迹分析来测量瘦素信号的激活状态。我们观察到内质网应激显著抑制瘦素诱导的STAT3磷酸化。相反,内质网应激不影响瘦素诱导的c-Jun氨基末端激酶激活。这些结果表明内质网应激诱导瘦素抵抗。内质网应激诱导的瘦素抵抗是通过蛋白酪氨酸磷酸酶1B介导的,而不是通过细胞因子信号转导抑制因子3介导的。值得注意的是,一种可以提高蛋白质折叠能力的化学伴侣可逆转内质网应激诱导的瘦素抵抗。此外,诱导内质网应激的同型半胱氨酸在体外和体内均导致瘦素抵抗。总之,这些发现表明瘦素抵抗的病理机制源于内质网应激。

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