Counter modulation of fatty acid-induced proinflammatory NFkB signalling in rat skeletal muscle cells by AMPK
Résumé
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. Here we show that exposure of L6 myotubes to palmitate, a saturated fatty acid, induces activation of the NFkB pathway (based on increased IKK phosphorylation, IkBa loss and elevated IL-6 mRNA expression) and that this was associated with enhanced phosphorylation/activation of p38 MAPK, JNK and ERK as well as impaired insulin-dependent activation of PKB/Akt and glucose transport. NFkB activation by palmitate was unaffected by pharmacological inhibition of p38 MAPK or JNK, but was suppressed significantly by inhibition of MEK/ERK signalling. The importance of ERK with respect to downstream NFkB signalling was underscored by the finding that PMA, a potent ERK activator, enhanced IKK phosphorylation. Strikingly, both palmitate- and PMA-induced activation of IKK/NFkB were antagonised by AMPK activators because of reduced ERK signalling. Whilst palmitate-induced activation of NFkB was repressed by AMPK activation and by cellular over-expression of a mutated IκBα (S32A/S36A) super-repressor, this did not ameliorate the loss in insulin-stimulated PKB activation or glucose transport. Our data indicates that ERK plays a pivotal role in palmitate-induced activation of the IKK/NFkB signalling axis and that AMPK can restrain the activity of this proinflammatory pathway. The finding that insulin resistance persists in myotubes in which NFkB 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.
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