Figure 2.

Stress kinases mediate insulin resistance. Anabolic actions of insulin are mediated via the insulin receptor, which becomes autophosphorylated following binding to insulin. This allows for docking and tyrosine phosphorylation of insulin receptor substrate (IRS) proteins, which subsequently activate the downstream insulin signaling pathways. On the other hand, serine phosphorylation of IRS-1 and IRS-2 by stress-activated kinases JNK1 and IKKβ potently inhibits insulin signaling, resulting in cellular insulin resistance. Moreover, transcriptional activation of inflammatory genes by AP-1 and NF-κB, the transcription factors activated by the stress kinases, promotes insulin resistance in an autocrine and paracrine manner in metabolic tissues. In obesity, the increased influx of glucose and free fatty acids and production of ROS induces ER stress, resulting in activation of JNK signaling, whereas obesity-induced inflammation activates JNK and IKKβ signaling to promote insulin resistance. (This figure is from Odegaard and Chawla 2011; reprinted, with express permission, from the authors.)