Skeletal muscle-specific overproduction of constitutively activated c-Jun N-terminal kinase (JNK) induces insulin resistance in mice

Darren Colin Henstridge, Clinton R Bruce, C P Pang, Graeme I Lancaster, Tamara L Allen, Emma Estevez, Timothy Gardner, Jacquelyn M Weir, Peter J Meikle, Karen S L Lam, A Xu, N Fujii, L J Goodyear, Mark Anthony Febbraio

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Abstract

AIMS/HYPOTHESIS: 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/INTERPRETATION: 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.
Original languageEnglish
Pages (from-to)2769 - 2778
Number of pages10
JournalDiabetologia
Volume55
Issue number10
DOIs
Publication statusPublished - 2012

Cite this

Henstridge, Darren Colin ; Bruce, Clinton R ; Pang, C P ; Lancaster, Graeme I ; Allen, Tamara L ; Estevez, Emma ; Gardner, Timothy ; Weir, Jacquelyn M ; Meikle, Peter J ; Lam, Karen S L ; Xu, A ; Fujii, N ; Goodyear, L J ; Febbraio, Mark Anthony. / Skeletal muscle-specific overproduction of constitutively activated c-Jun N-terminal kinase (JNK) induces insulin resistance in mice. In: Diabetologia. 2012 ; Vol. 55, No. 10. pp. 2769 - 2778.
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title = "Skeletal muscle-specific overproduction of constitutively activated c-Jun N-terminal kinase (JNK) induces insulin resistance in mice",
abstract = "AIMS/HYPOTHESIS: 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/INTERPRETATION: 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.",
author = "Henstridge, {Darren Colin} and Bruce, {Clinton R} and Pang, {C P} and Lancaster, {Graeme I} and Allen, {Tamara L} and Emma Estevez and Timothy Gardner and Weir, {Jacquelyn M} and Meikle, {Peter J} and Lam, {Karen S L} and A Xu and N Fujii and Goodyear, {L J} and Febbraio, {Mark Anthony}",
year = "2012",
doi = "10.1007/s00125-012-2652-8",
language = "English",
volume = "55",
pages = "2769 -- 2778",
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Henstridge, DC, Bruce, CR, Pang, CP, Lancaster, GI, Allen, TL, Estevez, E, Gardner, T, Weir, JM, Meikle, PJ, Lam, KSL, Xu, A, Fujii, N, Goodyear, LJ & Febbraio, MA 2012, 'Skeletal muscle-specific overproduction of constitutively activated c-Jun N-terminal kinase (JNK) induces insulin resistance in mice', Diabetologia, vol. 55, no. 10, pp. 2769 - 2778. https://doi.org/10.1007/s00125-012-2652-8

Skeletal muscle-specific overproduction of constitutively activated c-Jun N-terminal kinase (JNK) induces insulin resistance in mice. / Henstridge, Darren Colin; Bruce, Clinton R; Pang, C P; Lancaster, Graeme I; Allen, Tamara L; Estevez, Emma; Gardner, Timothy; Weir, Jacquelyn M; Meikle, Peter J; Lam, Karen S L; Xu, A; Fujii, N; Goodyear, L J; Febbraio, Mark Anthony.

In: Diabetologia, Vol. 55, No. 10, 2012, p. 2769 - 2778.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Skeletal muscle-specific overproduction of constitutively activated c-Jun N-terminal kinase (JNK) induces insulin resistance in mice

AU - Henstridge, Darren Colin

AU - Bruce, Clinton R

AU - Pang, C P

AU - Lancaster, Graeme I

AU - Allen, Tamara L

AU - Estevez, Emma

AU - Gardner, Timothy

AU - Weir, Jacquelyn M

AU - Meikle, Peter J

AU - Lam, Karen S L

AU - Xu, A

AU - Fujii, N

AU - Goodyear, L J

AU - Febbraio, Mark Anthony

PY - 2012

Y1 - 2012

N2 - AIMS/HYPOTHESIS: 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/INTERPRETATION: 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.

AB - AIMS/HYPOTHESIS: 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/INTERPRETATION: 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.

UR - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22832498

U2 - 10.1007/s00125-012-2652-8

DO - 10.1007/s00125-012-2652-8

M3 - Article

VL - 55

SP - 2769

EP - 2778

JO - Diabetologia

JF - Diabetologia

SN - 0012-186X

IS - 10

ER -