Endoplasmic reticulum stress and inflammation in obesity and type 2 diabetes

Metabolic and immune systems are among the most fundamental requirements for survival, and mechanisms integrating and co-ordinating the activities of these responses have been evolutionarily highly conserved throughout the species. Disruption of the interface between inflammatory and metabolic pathways, most notably insulin action, is central to the pathogenesis of a cluster of chronic metabolic diseases, particularly obesity, insulin resistance, type 2 diabetes and cardiovascular disease, which collectively constitute the greatest threat to the global human health and welfare. The c-Jun N-terminal kinase (JNK) is a critical mediator linking inflammatory signals to insulin resistance in obesity. In recent years, we have demonstrated that endoplasmic reticulum (ER) dysfunction and the integrated stress responses are important in the emergence of abnormal JNK activity, inflammatory responses, and insulin resistance in obesity. BlockingJNK activity through chemical of genetic means or targeting ER function through chemical chaperones or by genetics leads to marked metabolic improvement and normalization of glucose metabolism in mice models of obesity.