title: Double-stranded RNA-activated protein kinase is a key modulator of insulin sensitivity in physiological conditions and in obesity in mice.
abstract: 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.
authors.affiliation: Department of Internal Medicine, State University of Campinas, São Paulo, Brazil.
authors.forename: M A
authors.initials: MA
authors.lastname: Carvalho-Filho
authors.forename: B M
authors.initials: BM
authors.lastname: Carvalho
authors.forename: A G
authors.initials: AG
authors.lastname: Oliveira
authors.forename: D
authors.initials: D
authors.lastname: Guadagnini
authors.forename: M
authors.initials: M
authors.lastname: Ueno
authors.forename: M M
authors.initials: MM
authors.lastname: Dias
authors.forename: D M
authors.initials: DM
authors.lastname: Tsukumo
authors.forename: S M
authors.initials: SM
authors.lastname: Hirabara
authors.forename: L F
authors.initials: LF
authors.lastname: Reis
authors.forename: R
authors.initials: R
authors.lastname: Curi
authors.forename: J B C
authors.initials: JB
authors.lastname: Carvalheira
authors.forename: Mario J A
authors.initials: MJ
authors.lastname: Saad
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism; D004435:Eating / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000502:physiology; D019308:Palmitic Acid / Q000494:pharmacology; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D012330:RNA, Double-Stranded; D019308:Palmitic Acid; D051057:Proto-Oncogene Proteins c-akt; D019892:eIF-2 Kinase; D054648:Protein Phosphatase 2; D005947:Glucose