title: NF-kappaB-inducing kinase (NIK) mediates skeletal muscle insulin resistance: blockade by adiponectin.
abstract: Enhanced levels of nuclear factor (NF)-κB-inducing kinase (NIK), an upstream kinase in the NF-κB pathway, have been implicated in the pathogenesis of chronic inflammation in diabetes. We investigated whether increased levels of NIK could induce skeletal muscle insulin resistance. Six obese subjects with metabolic syndrome underwent skeletal muscle biopsies before and six months after gastric bypass surgery to quantitate NIK protein levels. L6 skeletal myotubes, transfected with NIK wild-type or NIK kinase-dead dominant negative plasmids, were treated with insulin alone or with adiponectin and insulin. Effects of NIK overexpression on insulin-stimulated glucose uptake were estimated using tritiated 2-deoxyglucose uptake. NF-κB activation (EMSA), phosphatidylinositol 3 (PI3) kinase activity, and phosphorylation of inhibitor κB kinase β and serine-threonine kinase (Akt) were measured. After weight loss, skeletal muscle NIK protein was significantly reduced in association with increased plasma adiponectin and enhanced AMP kinase phosphorylation and insulin sensitivity in obese subjects. Enhanced NIK expression in cultured L6 myotubes induced a dose-dependent decrease in insulin-stimulated glucose uptake. The decrease in insulin-stimulated glucose uptake was associated with a significant decrease in PI3 kinase activity and protein kinase B/Akt phosphorylation. Overexpression of NIK kinase-dead dominant negative did not affect insulin-stimulated glucose uptake. Adiponectin treatment inhibited NIK-induced NF-κB activation and restored insulin sensitivity by restoring PI3 kinase activation and subsequent Akt phosphorylation. These results indicate that NIK induces insulin resistance and further indicate that adiponectin exerts its insulin-sensitizing effect by suppressing NIK-induced skeletal muscle inflammation. These observations suggest that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Sealy Center of Molecular Medicine, 8.138 Medical Research Building, The University of Texas Medical Branch, 301 University Boulevard, Galveston, Texas 77555-1060, USA. sachoudh@utmb.edu
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Choudhary
authors.forename: Sandeep
authors.initials: S
authors.lastname: Sinha
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Srijita
authors.initials: S
authors.lastname: Banerjee
authors.forename: Padma
authors.initials: P
authors.lastname: Sathyanarayana
authors.forename: Sadeka
authors.initials: S
authors.lastname: Shahani
authors.forename: Vadim
authors.initials: V
authors.lastname: Sherman
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Tilton
authors.forename: Mandeep
authors.initials: M
authors.lastname: Bajaj
mesh_terms: D052242:Adiponectin / Q000494:pharmacology*; D000328:Adult; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D052242:Adiponectin; D005947:Glucose; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D000097782:NF-kappaB-Inducing Kinase