Knockout of inositol-requiring enzyme 1α in pro-opiomelanocortin neurons decreases fat mass via increasing energy expenditure

Although numerous functions of inositol-requiring enzyme 1α (IRE1α) have been identified, a role of IRE1α in pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus is largely unknown. Here, we showed that mice lacking IRE1α specifically in POMC neurons (PIKO) are lean and resistant to high-fat diet-induced obesity and obesity-related insulin resistance, liver steatosis and leptin resistance. Furthermore, PIKO mice had higher energy expenditure, probably due to increased thermogenesis in brown adipose tissue. Additionally, α-melanocyte-stimulating hormone production was increased in the hypothalamus of PIKO mice. These results demonstrate that IRE1α in POMC neurons plays a critical role in the regulation of obesity and obesity-related metabolic disorders. Our results also suggest that IRE1α is not only an endoplasmic reticulum stress sensor, but also a new potential therapeutic target for obesity and obesity-related metabolic diseases.