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The IRE1?-XBP1s pathway promotes insulin-stimulated glucose uptake in adipocytes by increasing PPAR? activity.


ABSTRACT: The peroxisome proliferator-activated receptor-? (PPAR?) 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? expression during adipogenesis. In this study, we investigated the role of XBP1s, particularly with respect to PPAR?, in the mechanisms underlying insulin sensitivity in mature adipocytes. Insulin was able to stimulate XBP1s generation by activating inositol-requiring enzyme 1 (IRE1) ? 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? 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 ?, 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? activation.

SUBMITTER: Cho YM 

PROVIDER: S-EPMC6093883 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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The IRE1α-XBP1s pathway promotes insulin-stimulated glucose uptake in adipocytes by increasing PPARγ activity.

Cho Yoon Mi YM   Kim Dong Hee DH   Lee Kyung Hye KH   Jeong Seong-Whan SW   Kwon Oh-Joo OJ  

Experimental & molecular medicine 20180815 8


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 stimula  ...[more]

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