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

Cell Reports

Kenji Uno¹  Toru Suzuki¹  Junhong Gao¹  Kei Takahashi¹  Tomohito Izumi¹  Keiichi Kondo¹  Shojiro Sawada¹  Tetsuya Yamada¹  Sohei Tsukita¹  Junta Imai¹  Keizo Kaneko¹  Hideki Katagiri¹  Atsuko Asao²  Naoto Ishii²  Yasushi Ishigaki³  Seiichi Oyadomari⁴ 

[1] Department of Metabolism and Diabetes, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan;Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi 980-8575, Japan;Division of Diabetes and Metabolism, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate 020-8505, Japan;Division of Molecular Biology, Institute for Genome Research, University of Tokushima, 3-18-15 Kuramoto, Tokushima 770-8503, Japan;

关键词: ER stress;    adipose tissue macrophage;    macrophage polarization;    insulin resistance;    M2 macrophage;   

DOI  :  10.1016/j.celrep.2017.01.076

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown