Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB signalling in rat skeletal muscle cells by AMP-activated protein kinase
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Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB 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.
I: Biochemical Journal, Bind 435, Nr. 2, 15.04.2011, s. 463-474.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Counter-modulation of fatty acid-induced pro-inflammatory nuclear factor κB 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
Y1 - 2011/4/15
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-κB (nuclear factor κB) pathway {based on increased IKK [IκB (inhibitory κB) kinase] phosphorylation, IκBα 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) aswell as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-κB 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-κB signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/NF-κB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-κB was repressed by AMPK activation and by cellular overexpression of a mutated IκBα (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-κB signalling axis and that AMPK can restrain the activity of this proinflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-κB 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-κB (nuclear factor κB) pathway {based on increased IKK [IκB (inhibitory κB) kinase] phosphorylation, IκBα 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) aswell as impaired insulin-dependent activation of PKB (protein kinase B)/Akt and glucose transport. NF-κB 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-κB signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/NF-κB were antagonized by AMPK (AMP-activated protein kinase) activators because of reduced ERK signalling. Although palmitate-induced activation of NF-κB was repressed by AMPK activation and by cellular overexpression of a mutated IκBα (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-κB signalling axis and that AMPK can restrain the activity of this proinflammatory pathway. The finding that insulin resistance persists in myotubes in which NF-κB 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 - Fatty acid
KW - Glucose transport
KW - Insulin
KW - Insulin resistance
KW - Nuclear factor κB (NF-κB)
KW - Protein kinase B (PKB)
UR - http://www.scopus.com/inward/record.url?scp=79953221811&partnerID=8YFLogxK
U2 - 10.1042/BJ20101517
DO - 10.1042/BJ20101517
M3 - Journal article
C2 - 21323644
AN - SCOPUS:79953221811
VL - 435
SP - 463
EP - 474
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 2
ER -
ID: 239568228