Novel insights in the interplay between inflammation and metabolic diseases: A role for the pathogen sensing kinase PKR

Abstract

COMMENTARY ON: Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS. Cell 140, 338–348, February 5, 2010. Copyright 2010. Abstract reprinted with permission from Elsevier . http://www.ncbi.nlm.nih.gov/pubmed/20144759 Abstract: As chronic inflammation is a hallmark of obesity, pathways that integrate nutrient- and pathogen sensing pathways are of great interest in understanding the mechanisms of insulin resistance, type 2 diabetes, and other chronic metabolic pathologies. Here, Nakamura et al. provide evidence that double-stranded RNA-dependent protein kinase (PKR) can respond to nutrient signals as well as endoplasmic reticulum (ER) stress and coordinate the activity of other critical inflammatory kinases such as the c-Jun N-terminal kinase (JNK) to regulate insulin action and metabolism. PKR also directly targets and modifies insulin receptor substrate and hence integrates nutrients and insulin action with a defined pathogen response system. Dietary and genetic obesity features marked activation of PKR in adipose and liver tissues and absence of PKR alleviates metabolic deterioration due to nutrient or energy excess in mice. These findings demonstrate PKR as a critical component of an inflammatory complex that responds to nutrients and organelle dysfunction .