title: Constitutive STAT3 phosphorylation contributes to skeletal muscle insulin resistance in type 2 diabetes.
abstract: Signal transducer and activator of transcription 3 (STAT3) is involved in cytokine- and nutrient-induced insulin resistance. The role of STAT3 in the development of skeletal muscle insulin resistance and type 2 diabetes (T2D) pathogenesis is incompletely defined. We tested the hypothesis that STAT3 signaling contributes to skeletal muscle insulin resistance in T2D. Protein abundance and phosphorylation of STAT3 signaling molecules were determined in skeletal muscle biopsy specimens from BMI- and age-matched overweight individuals with normal glucose tolerant (NGT) and T2D patients. The direct role of STAT3 in the development of lipid-induced skeletal muscle insulin resistance was determined using small interfering (si)RNA. Phosphorylated STAT3, phosphorylated Janus kinase 2 (JAK2), and suppressor of cytokine signaling 3 (SOCS3) protein abundance was increased in skeletal muscle from T2D patients. STAT3 phosphorylation positively correlated with free fatty acid level and measures of insulin sensitivity in NGT but not T2D patients. Palmitate exposure led to a constitutive phosphorylation of STAT3, increased protein abundance of SOCS3, and development of insulin resistance in L6 myotubes. These effects were prevented by siRNA-mediated STAT3 silencing. In summary, STAT3 is constitutively phosphorylated in skeletal muscle from T2D patients. STAT3 gene silencing prevents lipid-induced insulin resistance in cultured myotubes. Collectively, our results implicate excessive STAT3 signaling in the development of skeletal muscle insulin resistance in T2D.
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredirick
authors.initials: F
authors.lastname: Mashili
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Chibalin
authors.forename: Anna
authors.initials: A
authors.lastname: Krook
authors.forename: Juleen R
authors.initials: JR
authors.lastname: Zierath
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D053614:Janus Kinase 2 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D050177:Overweight / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: D005230:Fatty Acids, Nonesterified; C106644:SOCS3 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; C507924:JAK2 protein, human; D053614:Janus Kinase 2