The Metabolic ER Stress Sensor IRE1α Suppresses Alternative Activation of Macrophages to Impair Energy Expenditure in Obesity

Obesity is associated with metabolic inflammation and endoplasmic reticulum (ER) stress that are believed to promote metabolic disease progression. Adipose tissue macrophages (ATMs) are key players in orchestrating metabolic inflammation, and ER stress is able to enhance macrophage activation. However, whether ER stress-activated unfolded protein response (UPR) pathways underlie ATM regulation of glucose and energy homeostasis remains unclear. Here we identified inositol-requiring enzyme 1α (IRE1α) as a critical switch that governs M1/M2 macrophage polarization and energy balance. Myeloid-specific deletion of Ire1α (IRE1αLysM 41 ) in 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. Remarkably, brown adipose tissue (BAT) activity, WAT browning, and energy expenditure were significantly higher in IRE1αLysM mice than in their IRE1αf/f 45 littermates. Furthermore, ablation of IRE1α cell-autonomously augmented M2 polarization, while dampening M1 polarization, of macrophages. These results indicate that IRE1α functions as a molecular sensor for protein unfolding, metabolic, and immunological states to guide ATM polarization. The macrophage IRE1α pathway of ER stress drives obesity and metabolic syndrome, at least in part through impairing BAT activity and WAT browning.