Gökhan S. Hotamisligil
Nature 444, 860-867 (14 December 2006)
Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.
IRS-1 and 2 are crucial signalling molecules in insulin action. Activation of JNK by cytokine signalling, lipid products, ROS or through IRE1 during ER stress leads to serine phosphorylation of IRS-1 and 2, and consequently inhibits insulin signalling. Similar signals, including PERK, also activate IKK and inhibition of insulin action through a series of transcriptional events mediated by NF-B. JNK also regulates transcription through AP-1. Lipid-activated transcriptional events are mediated by nuclear hormone receptors PPAR and LXR. The biological activities of lipids are regulated by FABPs that function as chaperones. Mitochondria and the ER can both contribute to ROS production. ATF6 and XBP1 are critical regulators of ER function and its adaptive responses.
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