Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor kappa B signalling in rat skeletal muscle cells by AMP-activated protein kinase

Charlotte J. Green, Katherine Macrae, Sarah Fogarty, D. Grahame Hardie, Kei Sakamoto, Harinder S. Hundal (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    53 Citations (Scopus)

    Abstract

    Sustained over-supply of saturated non-esterified 'free' fatty acids has been shown to promote skeletal muscle insulin resistance, which may be driven, in part, by an increase in inflammatory signalling within this tissue. In the present manuscript we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NF-kappa B (nuclear factor kappa B) pathway {based on increased IKK [I kappa B (inhibitory kappa B) kinase] phosphorylation, I kappa B alpha loss and elevated interleukin-6 mRNA expression} and that this was associated with enhanced phosphorylation/activation of p38 MAPK (mitogen-activated protein kinase), JNK (c-Jun N-terminal kinase) and ERK (extracellular-signal-regulated kinase) as well as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-kappa B activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK (MAPK/ERK kinase)/ERK signalling. The importance of ERK with respect to downstream NF-kappa B signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/N kappa-KB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-kappa B was repressed by AMPK activation and by cellular overexpression of a mutated I kappa B alpha (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our results from the present study indicate that ERK plays a pivotal role in palmitate-induced activation of the IKK/NF-kappa B signalling axis and that AMPK can restrain the activity of this proinflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-kappa B signalling has been repressed implies that palmitate and/or its lipid derivatives retain the capacity to impair insulin-regulated events independently of the increase in inflammatory signalling.

    Original languageEnglish
    Pages (from-to)463-474
    Number of pages12
    JournalBiochemical Journal
    Volume435
    Issue number2
    DOIs
    Publication statusPublished - 15 Apr 2011

    Keywords

    • glucose transport
    • insulin
    • insulin resistance
    • fatty acid
    • nuclear factor kappa B (NF-kappa B)
    • protein kinase B (PKB)
    • INDUCED INSULIN-RESISTANCE
    • DEPENDENT ACTIVATION
    • EPITHELIAL-CELLS
    • GENE-EXPRESSION
    • L6 MYOTUBES
    • P38 MAPK
    • IKK-BETA
    • PALMITATE
    • RECEPTOR
    • ALPHA

    Cite this

    @article{709c3e794df142cba57d8eb61cf97ac5,
    title = "Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor kappa B signalling in rat skeletal muscle cells by AMP-activated protein kinase",
    abstract = "Sustained over-supply of saturated non-esterified 'free' fatty acids has been shown to promote skeletal muscle insulin resistance, which may be driven, in part, by an increase in inflammatory signalling within this tissue. In the present manuscript we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NF-kappa B (nuclear factor kappa B) pathway {based on increased IKK [I kappa B (inhibitory kappa B) kinase] phosphorylation, I kappa B alpha loss and elevated interleukin-6 mRNA expression} and that this was associated with enhanced phosphorylation/activation of p38 MAPK (mitogen-activated protein kinase), JNK (c-Jun N-terminal kinase) and ERK (extracellular-signal-regulated kinase) as well as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-kappa B activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK (MAPK/ERK kinase)/ERK signalling. The importance of ERK with respect to downstream NF-kappa B signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/N kappa-KB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-kappa B was repressed by AMPK activation and by cellular overexpression of a mutated I kappa B alpha (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our results from the present study indicate that ERK plays a pivotal role in palmitate-induced activation of the IKK/NF-kappa B signalling axis and that AMPK can restrain the activity of this proinflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-kappa B signalling has been repressed implies that palmitate and/or its lipid derivatives retain the capacity to impair insulin-regulated events independently of the increase in inflammatory signalling.",
    keywords = "glucose transport, insulin, insulin resistance, fatty acid, nuclear factor kappa B (NF-kappa B), protein kinase B (PKB), INDUCED INSULIN-RESISTANCE, DEPENDENT ACTIVATION, EPITHELIAL-CELLS, GENE-EXPRESSION, L6 MYOTUBES, P38 MAPK, IKK-BETA, PALMITATE, RECEPTOR, ALPHA",
    author = "Green, {Charlotte J.} and Katherine Macrae and Sarah Fogarty and Hardie, {D. Grahame} and Kei Sakamoto and Hundal, {Harinder S.}",
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    Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor kappa B signalling in rat skeletal muscle cells by AMP-activated protein kinase. / Green, Charlotte J.; Macrae, Katherine; Fogarty, Sarah; Hardie, D. Grahame; Sakamoto, Kei; Hundal, Harinder S. (Lead / Corresponding author).

    In: Biochemical Journal, Vol. 435, No. 2, 15.04.2011, p. 463-474.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor kappa B signalling in rat skeletal muscle cells by AMP-activated protein kinase

    AU - Green, Charlotte J.

    AU - Macrae, Katherine

    AU - Fogarty, Sarah

    AU - Hardie, D. Grahame

    AU - Sakamoto, Kei

    AU - Hundal, Harinder S.

    PY - 2011/4/15

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    N2 - Sustained over-supply of saturated non-esterified 'free' fatty acids has been shown to promote skeletal muscle insulin resistance, which may be driven, in part, by an increase in inflammatory signalling within this tissue. In the present manuscript we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NF-kappa B (nuclear factor kappa B) pathway {based on increased IKK [I kappa B (inhibitory kappa B) kinase] phosphorylation, I kappa B alpha loss and elevated interleukin-6 mRNA expression} and that this was associated with enhanced phosphorylation/activation of p38 MAPK (mitogen-activated protein kinase), JNK (c-Jun N-terminal kinase) and ERK (extracellular-signal-regulated kinase) as well as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-kappa B activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK (MAPK/ERK kinase)/ERK signalling. The importance of ERK with respect to downstream NF-kappa B signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/N kappa-KB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-kappa B was repressed by AMPK activation and by cellular overexpression of a mutated I kappa B alpha (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our results from the present study indicate that ERK plays a pivotal role in palmitate-induced activation of the IKK/NF-kappa B signalling axis and that AMPK can restrain the activity of this proinflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-kappa B signalling has been repressed implies that palmitate and/or its lipid derivatives retain the capacity to impair insulin-regulated events independently of the increase in inflammatory signalling.

    AB - Sustained over-supply of saturated non-esterified 'free' fatty acids has been shown to promote skeletal muscle insulin resistance, which may be driven, in part, by an increase in inflammatory signalling within this tissue. In the present manuscript we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NF-kappa B (nuclear factor kappa B) pathway {based on increased IKK [I kappa B (inhibitory kappa B) kinase] phosphorylation, I kappa B alpha loss and elevated interleukin-6 mRNA expression} and that this was associated with enhanced phosphorylation/activation of p38 MAPK (mitogen-activated protein kinase), JNK (c-Jun N-terminal kinase) and ERK (extracellular-signal-regulated kinase) as well as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-kappa B activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK (MAPK/ERK kinase)/ERK signalling. The importance of ERK with respect to downstream NF-kappa B signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/N kappa-KB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-kappa B was repressed by AMPK activation and by cellular overexpression of a mutated I kappa B alpha (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our results from the present study indicate that ERK plays a pivotal role in palmitate-induced activation of the IKK/NF-kappa B signalling axis and that AMPK can restrain the activity of this proinflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-kappa B signalling has been repressed implies that palmitate and/or its lipid derivatives retain the capacity to impair insulin-regulated events independently of the increase in inflammatory signalling.

    KW - glucose transport

    KW - insulin

    KW - insulin resistance

    KW - fatty acid

    KW - nuclear factor kappa B (NF-kappa B)

    KW - protein kinase B (PKB)

    KW - INDUCED INSULIN-RESISTANCE

    KW - DEPENDENT ACTIVATION

    KW - EPITHELIAL-CELLS

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    KW - L6 MYOTUBES

    KW - P38 MAPK

    KW - IKK-BETA

    KW - PALMITATE

    KW - RECEPTOR

    KW - ALPHA

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