Double-Stranded RNA-Activated Protein Kinase Is a Key Modulator of Insulin Sensitivity in Physiological Conditions and in Obesity in Mice

• Published in: Endocrinology (Philadelphia) 2012-11, Vol.153 (11), p.5261-5274
• Main Authors: Carvalho-Filho, M. A, Carvalho, B. M, Oliveira, A. G, Guadagnini, D, Ueno, M, Dias, M. M, Tsukumo, D. M, Hirabara, S. M, Reis, L. F, Curi, R, Carvalheira, J. B.C, Saad, Mario J.A
• Format: Article
• Language: English
• Subjects: Adipose tissue; AKT protein; Animals; Biological and medical sciences; Blood Glucose - genetics; Blood Glucose - metabolism; c-Jun protein; Crosstalk; Diet; Double-stranded RNA; Eating - physiology; eIF-2 kinase; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Enzyme inhibitors; Fundamental and applied biological sciences. Psychology; Glucose; Glucose - metabolism; Glucose Intolerance - genetics; Glucose Intolerance - metabolism; Glucose tolerance; High fat diet; Innate immunity; Insulin; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Insulin resistance; Insulin Resistance - physiology; JNK protein; Kinases; Liver - drug effects; Liver - metabolism; Macrophages - drug effects; Macrophages - metabolism; Medical sciences; Metabolic diseases; Metabolic pathways; Metabolism; Mice; Mice, Knockout; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Obesity; Obesity - genetics; Obesity - metabolism; Oxygen Consumption - physiology; Palmitic Acid - pharmacology; Pathogens; Phosphatase; Phosphoprotein phosphatase; Phosphorylation; Physiology; Protein kinase; Protein phosphatase; Protein Phosphatase 2 - metabolism; Protein turnover; Protein-serine/threonine kinase; Proteins; Proto-Oncogene Proteins c-akt - metabolism; RNA, Double-Stranded - genetics; RNA, Double-Stranded - metabolism; Sensitivity; Signal transduction; Signal Transduction - drug effects; Substrate inhibition; Thymoma; Transcription factors; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2012-1400

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.