Furthermore, migration of inflammatory cells to obese adipose tissue, particularly at later stages of the disease, may contribute to and possibly propagate inflammatory responses . Alterations in lipids and lipid mediators represent another potential component of both inflammatory responses and insulin resistance in obesity . Recently, several mechanistic models have been proposed to explain the emergence of inflammatory and stress responses in obesity and type 2 diabetes, including organelle dysfunction influencing mitochondria and endoplasmic reticulum and associated stress signaling pathways . While it has yet to be determined whether inflammatory and stress signaling pathways are proximal or distal to organelle dysfunction or triggered by peptide or lipid mediators, it is evident that many of these harmful responses have common targets in regulating insulin receptor signaling. One such target is insulin receptor substrate 1 serine phosphorylation which is mediated by inflammatory kinases such as c-Jun N-terminal kinase and IkB kinase beta and consequently modulates insulin action . Pharmacological inhibition or genetic ablation of either JNK1 or IKKb is effective in the treatment of experimental insulin resistance and diabetes . JNK, a member of the mitogen-activated protein kinase family, is activated by a wide variety of stimuli, including cytokines and environmental stress. Previous work by our laboratory and others has shown that JNK1 is necessary for TNF-a induced serine phosphorylation of IRS-1 and insulin resistance in cells and animals . Whole body genetic deficiency of JNK1, but not JNK2, results in marked protection against insulin resistance and hepatosteosis induced by obesity . JNK activity has also been Adriamycin linked to adverse metabolic outcomes in several critical cellular models and tissues. For example, in b-cells of the islet of Langerhans, activation of JNK is involved in the VE-821 in vivo reduction of insulin gene expression and suppression of the JNK pathway protects b-cells against oxidative stress . Additionally, inhibition of JNK activity in liver cells using either dominant negative JNK1 or shRNA against JNK1 lowers circulating glucose and insulin levels and increases insulin sensitivity in obese models . In contrast, JNK1 activity has little effect on muscle glycogen levels or the protein levels of key molecules involved in glucose metabolism, suggesting that enhanced skeletal muscle glucose metabolism may not underlie the direct beneficial effects of JNK1-deficiency in mice . The combined results of these studies reveal that JNK1 activity has differential effects on metabolic disease depending upon tissue and cell type examined. Adipose tissue inflammation is a critical pathophysiological mechanism underlying obesity-induced metabolic changes and immune cells infiltrate adipose tissue during the late stages of obesity.