The IRE1α-XBP1s pathway promotes insulin-stimulated glucose uptake in adipocytes by increasing PPARγ activity.
The IRE1α-XBP1s pathway promotes insulin-stimulated glucose uptake in adipocytes by increasing PPARγ activity.
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DOI：
10.1038/s12276-018-0131-0
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发表时间：
2018-08-15
影响因子：
12.8
通讯作者：
Kwon OJ
中科院分区：
文献类型：
--
作者：
Cho YM;Kim DH;Lee KH;Jeong SW;Kwon OJ
过氧化物酶体增殖物激活受体γ(PPARγ)通过调节成熟脂肪细胞的成脂和代谢功能，改善全身胰岛素敏感性。我们之前已经证明，在脂肪形成过程中，X-box结合蛋白1的活性剪接变异体(XBP1s)可以增强PPARγ的表达。在这项研究中，我们研究了XBP1s，特别是与PPARγ有关的作用，在成熟脂肪细胞胰岛素敏感性的机制中。胰岛素通过激活肌醇需要酶1(IRE1)α刺激XBP1s的生成，并通过诱导核转位增加其转录活性。XBP1还上调了磷酸化IRS1和AKT的水平，证明了一种连接胰岛素和XBP1s的正反馈调节机制。XBP促进成纤维细胞生长因子21的表达，进而增加PPARγ活性、GLUT4向细胞表面的移位和脂肪细胞的葡萄糖摄取率。此外，XBP1s通过增加脂联素的分泌，抑制促炎症脂肪因子如瘦素、单核细胞趋化蛋白1和肿瘤坏死因子α的分泌，减少脂肪酸的释放，从而消除棕榈酸诱导的脂肪细胞胰岛素抵抗。这些发现为XBP1通过诱导成纤维细胞生长因子21和PPARγ激活来刺激脂肪细胞的胰岛素敏感性提供了新的机制。研究人员已经确定了一种名为XBP1s的蛋白质，它可能通过使细胞对胰岛素重新敏感来帮助治疗II型糖尿病。胰岛素通过触发细胞从血液中吸收糖分来控制血糖水平。在肥胖者中，细胞可能对胰岛素失去敏感性，需要增加数量来触发糖吸收，扰乱血糖调节。这被称为胰岛素抵抗，是II型糖尿病和其他疾病的主要危险因素。此前已知XBP1s会影响胰岛素敏感性，但机制尚不清楚。首尔韩国天主教大学的权吴珠和他的同事研究了XBP1是如何影响小鼠脂肪细胞对胰岛素的反应的。他们发现，XBP1恢复了胰岛素敏感性，将胰岛素抵抗细胞转变为通过吸收糖分对胰岛素做出反应的细胞。XBP1可能在治疗或预防II型糖尿病方面有用。
The peroxisome proliferator-activated receptor-γ (PPARγ) improves whole-body insulin sensitivity by regulating the adipogenic and metabolic functions of mature adipocytes. We have previously demonstrated that an active splice variant of X-box binding protein 1 (XBP1s) enhances PPARγ expression during adipogenesis. In this study, we investigated the role of XBP1s, particularly with respect to PPARγ, in the mechanisms underlying insulin sensitivity in mature adipocytes. Insulin was able to stimulate XBP1s generation by activating inositol-requiring enzyme 1 (IRE1) α and was also able to increase its transcriptional activity by inducing nuclear translocation. XBP1s also upregulated the levels of phosphorylated IRS1 and AKT, demonstrating a positive feedback regulatory mechanism linking insulin and XBP1s. XBP1s enhanced the expression of fibroblast growth factor 21 and, in turn, increased PPARγ activity, translocation of GLUT4 to the cell surface, and glucose uptake rate in adipocytes. In addition, XBP1s abolished palmitate-induced insulin resistance in adipocytes by increasing adiponectin secretion, repressing the secretion of pro-inflammatory adipokines such as leptin, monocyte chemoattractant protein 1, and tumor necrosis factor α, and decreasing fatty acid release. These findings provide a novel mechanism by which XBP1s stimulate insulin sensitivity in adipocytes through fibroblast growth factor 21 induction and PPARγ activation. Researchers have identified a protein, XBP1s, that may help treat type II diabetes by re-sensitizing cells to insulin. Insulin controls blood sugar levels by triggering cells to absorb sugar from the blood. In obese individuals, cells can lose sensitivity to insulin, requiring increasing quantities to trigger sugar uptake, disrupting blood sugar regulation. Termed insulin resistance, this is a major risk factor for type II diabetes and other diseases. XBP1s was previously known to affect insulin sensitivity, but the mechanism was unclear. Oh-Joo Kwon and co-workers at The Catholic University of Korea in Seoul investigated how XBP1s affected the response of mouse fat cells to insulin. They found that XBP1s restored insulin sensitivity, turning insulin-resistant cells into cells that responded to insulin by absorbing sugar. XBP1s may be useful in treatment or prevention of type II diabetes.