Although endoplasmic reticulum (ER) stress and metabolic inflammation are associated with the development of obesity, whether the two processes converge to disrupt energy homeostasis during progression of the disease was uncertain. Now, Shan et al. show that the inositol-requiring enzyme 1α (IRE1α; an ER stress sensor) pathway in adipose tissue macrophages (ATMs) drives the progression of obesity and the metabolic syndrome by reducing energy expenditure.

Having first shown that a high-fat diet (HFD) induced ER stress (demonstrated by activation of IRE1α) in parallel with adipose-tissue inflammation in mice, the researchers generated myeloid (bone-marrow-derived macrophage and peritoneal macrophage)-specific IRE1α-deficient mice to investigate possible metabolic actions of the IRE1α pathway during overnutrition. Remarkably, myeloid IRE1α deficiency prevented obesity, insulin resistance, hyperlipidaemia and hepatic steatosis induced by a HFD. These metabolically beneficial effects were accompanied by increases in brown adipose tissue activity, white adipose tissue browning and energy expenditure. Moreover, IRE1α deficiency increased M2 (anti-inflammatory) polarization of ATMs.

The findings suggest that, during overnutrition, IRE1α increases adipose tissue inflammation by guiding ATM polarization and drives obesity and the metabolic syndrome by impairing the thermogenic capacity of adipose tissue and thus energy expenditure. “Targeted modulation of IRE1α activity in ATMs might open new avenues for developing brown- and beige-fat-enhancing therapeutics to treat obesity and metabolic disease,” conclude the authors.