Resistin-like molecule β activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet
Resistin-like molecule β activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet
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DOI：
10.1074/jbc.m503065200
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发表时间：
2005-12-23
影响因子：
4.8
通讯作者：
Asano, T
中科院分区：
文献类型：
--
作者：
Kushiyama, A;Shojima, N;Asano, T
抵抗素及其类似分子(RELMs)是一个蛋白质家族，据报道与胰岛素抵抗和炎症有关。由于在胰岛素抵抗的啮齿动物模型中，RELmβ的血清浓度和肠道表达水平升高，本研究利用转基因小鼠和原代培养的肝细胞，研究了RELmβ对胰岛素信号和代谢的影响。首先，肝脏RELMβ过表达的转基因小鼠在喂食高脂饮食时表现出显著的高血糖、高脂血症、脂肪肝和胰岛增大。高胰岛素血症葡萄糖钳夹显示，由于肝脏葡萄糖产量增加，葡萄糖输注速率降低。此外，在RELMβ转基因小鼠中，IRS-1和IRS-2蛋白的表达水平以及胰岛素诱导的磷脂酰肌醇3-激酶和Akt的激活程度都降低了。在RELMβ长期处理(24 H)的原代培养肝细胞中也观察到类似的IRS-1和IRS-2蛋白下调，提示RELMβ诱导胰岛素抵抗的作用是直接的。在原代培养的肝细胞中，RELmβ能显著激活ERK和p38，而微弱地激活JNK。在RELMβ转基因小鼠的肝脏中也观察到了这种基础p38磷酸化水平的增加。综上所述，肠源性激素RELMβ可能通过激活经典的MAPK来影响胰岛素信号转导，其表达增加可能参与了某些胰岛素抵抗模型中糖耐量减低和高脂血症的发病机制。因此，RELMβ是评估胰岛素抵抗的一个潜在有用的标记物，也可能是未来新型抗糖尿病药物的靶点。
Resistin and resistin-like molecules (RELMs) are a family of proteins reportedly related to insulin resistance and inflammation. Because the serum concentration and intestinal expression level of RELM beta were elevated in insulin-resistant rodent models, in this study we investigated the effect of RELM beta on insulin signaling and metabolism using transgenic mice and primary cultured hepatocytes. First, transgenic mice with hepatic RELM beta overexpression were shown to exhibit significant hyperglycemia, hyperlipidemia, fatty liver, and pancreatic islet enlargement when fed a high fat diet. Hyperinsulinemic glucose clamp showed a decreased glucose infusion rate due to increased hepatic glucose production. In addition, the expression levels of IRS-1 and IRS-2 proteins as well as the degrees of insulin-induced phosphatidylinositol 3-kinase and Akt activations were attenuated in RELM beta transgenic mice. Similar down-regulations of IRS-1 and IRS-2 proteins were observed in primary cultured hepatocytes chronically treated (for 24 h) with RELM beta, suggesting the insulin resistance-inducing effect of RELM beta to be direct. Furthermore, it was shown that RELM beta acutely and markedly activates ERK and p38, while weakly activating JNK, in primary cultured hepatocytes. This increased basal p38 phosphorylation level was also observed in the livers of RELM beta transgenic mice. In conclusion, RELM beta, a gut-derived hormone, impairs insulin signaling probably via the activations of classic MAPKs, and increased expression of RELM beta may be involved in the pathogenesis of glucose intolerance and hyperlipidemia in some insulin-resistant models. Thus, RELM beta is a potentially useful marker for assessing insulin resistance and may also be a target for future novel anti-diabetic agents.