ER Stress Protein CHOP Mediates Insulin Resistance by Modulating Adipose Tissue Macrophage Polarity

Toru Suzuki, Junhong Gao, Yasushi Ishigaki, Keiichi Kondo, Shojiro Sawada, Tomohito Izumi, Kenji Uno, Keizo Kaneko, Sohei Tsukita, Kei Takahashi, Atsuko Asao, Naoto Ishii, Junta Imai, Tetsuya Yamada, Seiichi Oyadomari, Hideki Katagiri

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)

Abstract

Obesity represents chronic inflammatory states promoted by pro-inflammatory M1-macrophage infiltration into white adipose tissue (WAT), thereby inducing insulin resistance. Herein, we demonstrate the importance of an ER stress protein, CHOP, in determining adipose tissue macrophage (ATM) polarity and systemic insulin sensitivity. A high-fat diet (HFD) enhances ER stress with CHOP upregulation in adipocytes. CHOP deficiency prevents HFD-induced insulin resistance and glucose intolerance with ATM M2 predomination and Th2 cytokine upregulation in WAT. Whereas ER stress suppresses Th2 cytokine expression in cultured adipocytes, CHOP knockdown inhibits this downregulation. In contrast, macrophage responsiveness to Th1/Th2 cytokines is unchanged regardless of whether CHOP is expressed. Furthermore, bone marrow transplantation experiments showed recipient CHOP to be the major determinant of ATM polarity. Thus, CHOP in adipocytes plays important roles in ATM M1 polarization by altering WAT micro-environmental conditions, including Th2 cytokine downregulation. This molecular mechanism may link adipose ER stress with systemic insulin resistance.

Original languageEnglish
Pages (from-to)2045-2057
Number of pages13
JournalCell Reports
Volume18
Issue number8
DOIs
Publication statusPublished - 2017 Feb 21

Keywords

  • ER stress
  • M2 macrophage
  • adipose tissue macrophage
  • insulin resistance
  • macrophage polarization

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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