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

摘要

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. Diabetes: Restoring insulin sensitivity 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.