Retinoids ameliorate insulin resistance in a leptin-dependent manner in mice
Retinoids ameliorate insulin resistance in a leptin-dependent manner in mice
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DOI：
10.1002/hep.25798
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发表时间：
2012-10-01
期刊：
影响因子：
13.5
通讯作者：
Shiota, Goshi
中科院分区：
文献类型：
--
作者：
Tsuchiya, Hiroyuki;Ikeda, Yoshito;Shiota, Goshi
显性负性视黄酸受体（RAR）a特异性地在肝脏中表达的转基因小鼠表现出脂肪性肝炎，其导致肝脏肿瘤的发展。虽然这些小鼠脂肪性肝炎的原因尚不清楚，但胰岛素样生长因子-1的肝脏表达减少表明可能涉及胰岛素抵抗。在本研究中，我们研究了维甲酸对小鼠胰岛素抵抗的影响，以进一步了解这种情况的机制。全反式维甲酸（ATRA）可显著改善高脂、高果糖饮食诱导的非酒精性脂肪性肝病（NAFLD）模型C57 BL/6 J小鼠的胰岛素敏感性。在遗传性胰岛素抵抗的KK-Ay小鼠中观察到相同的效果，与瘦素信号传导途径蛋白的激活一致，包括信号转导和转录激活因子3（STAT 3）和Janus激酶2。然而，在瘦素缺乏的ob/ob小鼠中没有观察到这种效果。ATRA治疗显著上调NAFLD小鼠肝脏中的瘦素受体（LEPR）表达。与这些观察结果一致，体外实验表明，在存在瘦素的情况下，ATRA通过RAR α直接诱导LEPR基因表达，导致STAT 3和胰岛素诱导的胰岛素受体底物1磷酸化增强。选择性RAR α/β激动剂Am 80也增强了肝LEPR表达和STAT 3磷酸化，并改善了KK-Ay小鼠的胰岛素抵抗。结论：我们发现了一种未被认识到的机制，类维生素A的行动，激活肝脏瘦素信号，这导致增强胰岛素敏感性的两个小鼠模型的胰岛素抵抗。我们的数据表明，类维生素A可能具有治疗与胰岛素抵抗相关的NAFLD的潜力。（肝脏学2012）
Transgenic mice expressing dominant-negative retinoic acid receptor (RAR) a specifically in the liver exhibit steatohepatitis, which leads to the development of liver tumors. Although the cause of steatohepatitis in these mice is unknown, diminished hepatic expression of insulin-like growth factor-1 suggests that insulin resistance may be involved. In the present study, we examined the effects of retinoids on insulin resistance in mice to gain further insight into the mechanisms responsible for this condition. Dietary administration of all-trans-retinoic acid (ATRA) significantly improved insulin sensitivity in C57BL/6J mice, which served as a model for high-fat, high-fructose dietinduced nonalcoholic fatty liver disease (NAFLD). The same effect was observed in genetically insulin-resistant KK-Ay mice, occurring in concert with activation of leptin-signaling pathway proteins, including signal transducer and activator of transcription 3 (STAT3) and Janus kinase 2. However, such an effect was not observed in leptin-deficient ob/ob mice. ATRA treatment significantly up-regulated leptin receptor (LEPR) expression in the livers of NAFLD mice. In agreement with these observations, in vitro experiments showed that in the presence of leptin, ATRA directly induced LEPR gene expression through RARa, resulting in enhancement of STAT3 and insulin-induced insulin receptor substrate 1 phosphorylation. A selective RARa/beta agonist, Am80, also enhanced hepatic LEPR expression and STAT3 phosphorylation and ameliorated insulin resistance in KK-Ay mice. Conclusion: We discovered an unrecognized mechanism of retinoid action for the activation of hepatic leptin signaling, which resulted in enhanced insulin sensitivity in two mouse models of insulin resistance. Our data suggest that retinoids might have potential for treating NAFLD associated with insulin resistance. (HEPATOLOGY 2012)