| First Author | Shan B | Year | 2017 |
| Journal | Nat Immunol | Volume | 18 |
| Issue | 5 | Pages | 519-529 |
| PubMed ID | 28346409 | Mgi Jnum | J:259446 |
| Mgi Id | MGI:6142776 | Doi | 10.1038/ni.3709 |
| Citation | Shan B, et al. (2017) The metabolic ER stress sensor IRE1alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol 18(5):519-529 |
| abstractText | 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 1alpha (IRE1alpha) as a critical switch governing M1-M2 macrophage polarization and energy balance. Myeloid-specific IRE1alpha 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, IRE1alpha ablation augmented M2 polarization of macrophages in a cell-autonomous manner. Thus, IRE1alpha senses protein unfolding and metabolic and immunological states, and consequently guides ATM polarization. The macrophage IRE1alpha pathway drives obesity and metabolic syndrome through impairing BAT activity and WAT browning. |
