The molecular integration of nutrient- and pathogen-sensing pathways has become of great interest in understanding the mechanisms of
insulin resistance in
obesity. The
double-stranded RNA-dependent
protein kinase (PKR) is one candidate molecule that may provide cross talk between inflammatory and metabolic signaling. The present study was performed to determine, first, the role of PKR in modulating
insulin action and
glucose metabolism in physiological situations, and second, the role of PKR in
insulin resistance in obese mice. We used Pkr(-/-) and Pkr(+/+) mice to investigate the role of PKR in modulating
insulin sensitivity,
glucose metabolism, and
insulin signaling in liver, muscle, and adipose tissue in response to a high-fat diet. Our data show that in lean Pkr(-/-) mice, there is an improvement in
insulin sensitivity, and in
glucose tolerance, and a reduction in fasting
blood glucose, probably related to a decrease in
protein phosphatase 2A activity and a parallel increase in
insulin-induced
thymoma viral oncogene-1 (Akt) phosphorylation. PKR is activated in tissues of obese mice and can induce
insulin resistance by directly binding to and inducing
insulin receptor substrate (IRS)-1 serine307 phosphorylation or indirectly through modulation of
c-Jun N-terminal kinase and inhibitor of κB
kinase β. Pkr(-/-) mice were protected from high-fat diet-induced
insulin resistance and
glucose intolerance and showed improved
insulin signaling associated with a reduction in
c-Jun N-terminal kinase and inhibitor of κB
kinase β phosphorylation in
insulin-sensitive tissues. PKR may have a role in
insulin sensitivity under normal physiological conditions, probably by modulating
protein phosphatase 2A activity and
serine-threonine kinase phosphorylation, and certainly, this
kinase may represent a central mechanism for the integration of pathogen response and innate immunity with
insulin action and metabolic pathways that are critical in
obesity.