title: Skeletal muscle-specific overproduction of constitutively activated c-Jun N-terminal kinase (JNK) induces insulin resistance in mice.
abstract: OBJECTIVE
  Although skeletal muscle insulin resistance has been associated with activation of c-Jun N-terminal kinase (JNK), whether increased JNK activity causes insulin resistance in this organ is not clear. In this study we examined the metabolic consequences of isolated JNK phosphorylation in muscle tissue.
  
  
  METHODS
  Plasmids containing genes encoding a wild-type JNK1 (WT-JNK) or a JNK1/JNKK2 fusion protein (rendering JNK constitutively active; CA-Jnk) were electroporated into one tibialis anterior (TA) muscle of C57Bl/6 mice, with the contralateral TA injected with an empty vector (CON) to serve as a within-animal control.
  
  
  RESULTS
  Overproduction of WT-JNK resulted in a modest (~25%) increase in phosphorylation (Thr(183)/Tyr(185)) of JNK, but no differences were observed in Ser(307) phosphorylation of insulin receptor substrate 1 (IRS-1) or total IRS-1 protein, nor in insulin-stimulated glucose clearance into the TA muscle when comparing WT-JNK with CON. By contrast, overexpression of CA-Jnk, which markedly increased the phosphorylation of CA-JNK, also increased serine phosphorylation of IRS-1, markedly decreased total IRS-1 protein, and decreased insulin-stimulated phosphorylation of the insulin receptor (Tyr(1361)) and phosphorylation of Akt at (Ser(473) and Thr(308)) compared with CON. Moreover, overexpression of CA-Jnk decreased insulin-stimulated glucose clearance into the TA muscle compared with CON and these effects were observed without changes in intramuscular lipid species.
  
  
  CONCLUSIONS
  Constitutive activation of JNK in skeletal muscle impairs insulin signalling at the level of IRS-1 and Akt, a process which results in the disruption of normal glucose clearance into the muscle.
authors: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC, 3004, Australia.
authors: D C
authors: DC
authors: Henstridge
authors: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC, 3004, Australia.|Department of Physiology, Monash University, Clayton, VIC, Australia.
authors: C R
authors: CR
authors: Bruce
authors: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC, 3004, Australia.
authors: C P
authors: CP
authors: Pang
authors: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC, 3004, Australia.
authors: G I
authors: GI
authors: Lancaster
authors: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC, 3004, Australia.
authors: T L
authors: TL
authors: Allen
authors: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC, 3004, Australia.
authors: E
authors: E
authors: Estevez
authors: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC, 3004, Australia.
authors: T
authors: T
authors: Gardner
authors: Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
authors: J M
authors: JM
authors: Weir
authors: Metabolomics Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia.
authors: P J
authors: PJ
authors: Meikle
authors: Department of Medicine and Research Center for Heart, Brain, Hormones, and Healthy Aging, University of Hong Kong, Hong Kong, SAR, People's Republic of China.
authors: K S L
authors: KSL
authors: Lam
authors: Department of Medicine and Research Center for Heart, Brain, Hormones, and Healthy Aging, University of Hong Kong, Hong Kong, SAR, People's Republic of China.
authors: A
authors: A
authors: Xu
authors: Department of Health Promotion Science, Tokyo Metropolitan University, Hachioji, Tokyo, Japan.
authors: N
authors: N
authors: Fujii
authors: Joslin Diabetes Center, Boston, MA, USA.
authors: L J
authors: LJ
authors: Goodyear
authors: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, 75 Commercial Rd, Melbourne, VIC, 3004, Australia. mark.febbraio@bakeridi.edu.au.
authors: M A
authors: MA
authors: Febbraio
mesh_terms: D000818:Animals; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048031:JNK Mitogen-Activated Protein Kinases