Vaspin Is an Adipokine Ameliorating ER Stress in Obesity as a Ligand for Cell-Surface GRP78/MTJ-1 Complex

Abstract

It is unknown whether adipokines derived from adipose tissues modulate endoplasmic reticulum (ER) stress induced in obesity. Here, we show that visceral adipose tissue–derived serine protease inhibitor (vaspin) binds to cell-surface 78-kDa glucose-regulated protein (GRP78), which is recruited from ER to plasma membrane under ER stress. Vaspin transgenic mice were protected from diet-induced obesity, glucose intolerance, and hepatic steatosis, while vaspin-deficient mice developed glucose intolerance associated with upregulation of ER stress markers. With tandem affinity tag purification using HepG2 cells, we identified GRP78 as an interacting molecule. The complex formation of vaspin, GRP78, and murine tumor cell DnaJ-like protein 1 (MTJ-1) (DnaJ homolog, subfamily C, member 1) on plasma membrane was confirmed by cell-surface labeling with biotin and immunoprecipitation in liver tissues and H-4-II-E-C3 cells. The addition of recombinant human vaspin in the cultured H-4-II-E-C3 cells also increased the phosphorylation of Akt and AMP-activated protein kinase (AMPK) in a dose-dependent manner, and anti-GRP78 antibodies completely abrogated the vaspin-induced upregulation of pAkt and pAMPK. Vaspin is a novel ligand for cell-surface GRP78/MTJ-1 complex, and its subsequent signals exert beneficial effects on ER stress–induced metabolic dysfunctions.

Basic Residues of β-Sheet A Contribute to Heparin Binding and Activation of Vaspin (Serpin A12)

“…Insulin-resistant mouse models exhibit improved glucose tolerance after intraperitoneal vaspin application (3,4), and transgenic mice overexpressing vaspin are protected from diet-induced obesity and comorbidities, such as glucose intolerance, insulin resistance, and adipose tissue inflammation (5). We found that intraperitoneal and central administration of vaspin leads to reduced food intake and blood glucose in mice (6).…”

“…The full gel is shown for UFH, whereas for the other GAGs, only the complex bands are presented. The indicated bands are serpin-protease complex (1); active serpin (2); active, tag-cleaved serpin (3); cleaved serpin (4); and protease (5). Right, densitometric quantification of complex band intensities in relation to the molar ratio of GAG to vaspin of the gels on the left.…”

“…Previously, studies have reported cell surface localization of vaspin. It has been found enriched on the cell surface of H-4-II-E-C3 cells and in plasma membrane fractions of liver tissue in vaspin transgenic mice (5). There, it is thought to ameliorate hepatic oxidative stress via interaction with the endoplasmic reticulum chaperone GRP78.…”

“…In skin, vaspin expression by keratinocytes suppresses the expression and release of inflammatory cytokines by immune cells (11) and possibly regulates the activation of proinflammatory cytokines, such as chemerin, via KLK7 (12). Whereas vaspin-mediated improvement of glucose tolerance and reduction of food intake were found to be dependent on protease inhibition (4,13), anti-inflammatory effects in the liver have been linked to interaction with a membrane-associated endoplasmic reticulum chaperone protein (5).…”

Adipose tissue, obesity and adipokines: role in cancer promotion

“…According to Nakatuska and colleges, vaspin transgenic (Tg) mice fed a high fat-high sucrose (HFHS) diet were protected from increased adiposity, glucose intolerance, hepatic steatosis and obesity-induced inflammation [143]. Vaspin knockout mice, however, had opposite results with glucose intolerance, being highly associated with the upregulation of liver ER stress markers (marker of liver dysregulation) [143]. The effect of liver ER stress on insulin resistance/glucose intolerance in this model involved down regulation of ER chaperone proteins, such as 78 k-Da glucose-regulated protein (GRP78) [16].…”