Vaspin is an adipokine ameliorating ER stress in obesity as a ligand for cell-surface GRP78/MTJ-1 complex

Atsuko Nakatsuka, Jun Wada, Izumi Iseda, Sanae Teshigawara, Kanji Higashio, Kazutoshi Murakami, Motoko Kanzaki, Kentaro Inoue, Takahiro Terami, Akihiro Katayama, Kazuyuki Hida, Jun Eguchi, Chikage Sato Horiguchi, Daisuke Ogawa, Yasushi Matsuki, Ryuji Hiramatsu, Hideo Yagita, Shigeru Kakuta, Yoichiro Iwakura, Hirofumi Makino

Research output: Contribution to journalArticlepeer-review

66 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2823-2832
Number of pages10
JournalDiabetes
Volume61
Issue number11
DOIs
Publication statusPublished - Nov 2012

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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