| Title | The metabolic ER stress sensor IRE1 alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity |
| Authors | Shan, Bo Wang, Xiaoxia Wu, Ying Xu, Chi Xia, Zhixiong Dai, Jianli Shao, Mengle Zhao, Feng He, Shengqi Yang, Liu Zhang, Mingliang Nan, Fajun Li, Jia Liu, Jianmiao Liu, Jianfeng Jia, Weiping Qiu, Yifu Song, Baoliang Han, Jing-Dong J. Rui, Liangyou Duan, Sheng-Zhong Liu, Yong |
| Affiliation | Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Nutr & Metab,Inst Nutr Sci, Shanghai, Peoples R China. Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Computat Biol, Chinese Acad Sci Max Planck Partner Inst Computat, Shanghai, Peoples R China. Huazhong Univ Sci & Technol, Minist Educ, Key Lab Mol Biophys, Cellular Signaling Lab, Wuhan, Peoples R China. Univ Texas Southwestern Med Ctr Dallas, Dept Internal Med, Touchstone Diabet Ctr, Dallas, TX 75390 USA. Wuhan Univ, Inst Adv Studies, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan, Peoples R China. Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Shanghai Diabet Inst,Shanghai Key Lab Diabet Mell, Shanghai Clin Ctr Diabet,Dept Endocrinol & Metab, Shanghai, Peoples R China. Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, Shanghai, Peoples R China. Peking Univ, Beijing Key Lab Cardiometab Mol Med, Acad Adv Interdisciplinary Studies, Inst Mol Med,Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China. Univ Michigan, Med Sch, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Nutr & Metab,Inst Nutr Sci, Shanghai, Peoples R China. Liu, Y (reprint author), Wuhan Univ, Inst Adv Studies, Coll Life Sci, Hubei Key Lab Cell Homeostasis, Wuhan, Peoples R China. |
| Keywords | UNFOLDED PROTEIN RESPONSE ENDOPLASMIC-RETICULUM ADIPOSE-TISSUE BEIGE FAT POLARIZATION DISEASE INSULIN CELL THERMOGENESIS INFLAMMATION |
| Issue Date | 2017 |
| Publisher | NATURE IMMUNOLOGY |
| Citation | NATURE IMMUNOLOGY.2017,18(5),519-529. |
| Abstract | Obesity is associated with metabolic inflammation and endoplasmic reticulum (ER) stress, both of which promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players orchestrating metabolic inflammation, and ER stress enhances macrophage activation. However, whether ER stress pathways underlie ATM regulation of energy homeostasis remains unclear. Here, we identified inositol-requiring enzyme 1 alpha (IRE1 alpha) as a critical switch governing M1-M2 macrophage polarization and energy balance. Myeloid-specific IRE1 alpha abrogation in Ern1(f/f); Lyz2-Cre mice largely reversed high-fat diet (HFD)-induced M1-M2 imbalance in white adipose tissue (WAT) and blocked HFD-induced obesity, insulin resistance, hyperlipidemia and hepatic steatosis. Brown adipose tissue (BAT) activity, WAT browning and energy expenditure were significantly higher in Ern1(f/f); Lyz2-Cre mice. Furthermore, IRE1 alpha ablation augmented M2 polarization of macrophages in a cell-autonomous manner. Thus, IRE1 alpha senses protein unfolding and metabolic and immunological states, and consequently guides ATM polarization. The macrophage IRE1 alpha pathway drives obesity and metabolic syndrome through impairing BAT activity and WAT browning. |
| URI | http://hdl.handle.net/20.500.11897/473830 |
| ISSN | 1529-2908 |
| DOI | 10.1038/ni.3709 |
| Indexed | SCI(E) |
| Appears in Collections: | 分子医学研究所 |
