Attack of the kinases: JNK signaling in metabolism

The global rise in obesity has become a major health concern, in part due to the easy availability and consumption of high-calorie foods together with an increasingly sedentary lifestyle. More than a mere consequence of excess fat accumulation, obesity is now considered a complex health issue involving disrupted balance in how the body manages energy, primarily due to miscommunication between brain regions, such as the hypothalamus, and peripheral organs. One important aspect of this problem is how specific cell signaling pathways are disrupted by aberrant energy sensing and by oxidative stress-mediated damage and inflammation. Among these, AMP-activated protein kinase (AMPK) and c-Jun <i>N</i>-terminal kinase (JNK) have gained wide attention as key players that integrate nutrient-, hormone-, and inflammation-related signals. Here, we provide a comprehensive review of isoform-specific JNK functions, highlighting recent advances in the understanding of JNK1, JNK2, and JNK3 in hypothalamic circuits that govern energy balance, thermogenesis, and hepatic lipid metabolism. In addition, we also highlight the evolutionary and physiological significance of these kinase isoforms. Thus, this review encompasses current knowledge and key unanswered questions regarding the role of JNK in central and peripheral metabolic regulation.