Abstract
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.
Highlights
Adipose tissue is a key energy storage organ and is becoming known as an endocrine organ with multiple roles in metabolism and the regulation of whole-body energy homeostasis[1]
It is well known that GLUT4 redistribution is regulated by insulin receptor signaling pathways;[17,18] we examined whether X-box binding protein 1 (XBP1) is involved in the activation of insulin signaling in adipocytes
In this study, we provide the first evidence that XBP1s is produced by insulin signaling and is an active mediator of insulin-stimulated glucose uptake in adipocytes through its effects on Peroxisome proliferator-activated receptor-γ (PPARγ) activity
Summary
Adipose tissue is a key energy storage organ and is becoming known as an endocrine organ with multiple roles in metabolism and the regulation of whole-body energy homeostasis[1]. In conditions characterized by excessive energy, such as obesity, insulin resistance is locally initiated in adipose tissue and subsequently progresses to systemic insulin resistance. This systemic resistance is thought to be a major risk factor for metabolic disorders such as type 2 diabetes, fatty liver disease, atherosclerosis, and some cancers[2]. Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor that belongs to the. X-box binding protein 1 (XBP1) is a member of the bZIP family of transcription factors. XBP1 is converted to Official journal of the Korean Society for Biochemistry and Molecular Biology
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