KMID : 0620920180500080102
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Experimental & Molecular Medicine 2018 Volume.50 No. 8 p.102 ~ p.102
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The IRE1¥á-XBP1s pathway promotes insulin-stimulated glucose uptake in adipocytes by increasing PPAR¥ã activity
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Cho Yoon-Mi
Cho Yoon-Mi Lee Kyung-Hye Jeong Seong-Whan Kwon Oh-Joo
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Abstract
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The peroxisome proliferator-activated receptor-¥ã (PPAR¥ã) 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 PPAR¥ã expression during adipogenesis. In this study, we investigated the role of XBP1s, particularly with respect to PPAR¥ã, in the mechanisms underlying insulin sensitivity in mature adipocytes. Insulin was able to stimulate XBP1s generation by activating inositol-requiring enzyme 1 (IRE1) ¥á 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 PPAR¥ã 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 ¥á, 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 PPAR¥ã activation.
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KEYWORD
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Cell biology, Molecular biology
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