The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity
The metabolic ER stress sensor IRE1α suppresses alternative activation of macrophages and impairs energy expenditure in obesity
复制标题
代谢内质网应激传感器 IRE1 α 抑制巨噬细胞的替代激活并损害肥胖患者的能量消耗
DOI：
10.1038/ni.3709
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发表时间：
2017-05-01
影响因子：
30.5
通讯作者：
Liu, Yong
中科院分区：
文献类型：
--
作者：
Shan, Bo;Wang, Xiaoxia;Liu, Yong
肥胖与代谢性炎症和内质网应激有关，这两者都会促进代谢性疾病的进展。脂肪组织巨噬细胞(ATM)是协调代谢性炎症的关键分子，内质网应激可促进巨噬细胞的激活。然而，内质网应激通路是否构成ATM调节能量稳态的基础仍不清楚。在这里，我们确定肌醇需要酶1α(IRE1α)是调节M1-M2巨噬细胞极化和能量平衡的关键开关。髓系特异性IRE1α在Ern1中的消除(f/f)；Lyz2-CRE小鼠在很大程度上逆转了高脂饮食(HFD)诱导的白色脂肪组织(Wat)中M1-M2的失衡，并阻止了HFD诱导的肥胖、胰岛素抵抗、高脂血症和肝脏脂肪变性。Ern1(f/f)；Lyz2-Cre小鼠的棕色脂肪组织(BAT)活性、Wat褐变和能量消耗显著高于Ern1(f/f)；Lyz2-Cre小鼠。此外，IRE1α消融以细胞自主的方式增强巨噬细胞的M2极化。因此，IRE1α感知蛋白质的展开以及代谢和免疫状态，从而引导ATM极化。巨噬细胞IRE1α途径通过损害BAT活性和Wat褐变来驱动肥胖和代谢综合征。
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.