Abstract
Aims/HypothesisReduced skeletal muscle insulin sensitivity is a feature associated with sustained exposure to excess saturated fatty acids (SFA), whereas mono and polyunsaturated fatty acids (MUFA and PUFA) not only improve insulin sensitivity but blunt SFA-induced insulin resistance. The mechanisms by which MUFAs and PUFAs institute these favourable changes remain unclear, but may involve stimulating insulin signalling by counter-modulation/repression of protein phosphatase 2A (PP2A). This study investigated the effects of oleic acid (OA; a MUFA), linoleic acid (LOA; a PUFA) and palmitate (PA; a SFA) in cultured myotubes and determined whether changes in insulin signalling can be attributed to PP2A regulation.Principal FindingsWe treated cultured skeletal myotubes with unsaturated and saturated fatty acids and evaluated insulin signalling, phosphorylation and methylation status of the catalytic subunit of PP2A. Unlike PA, sustained incubation of rat or human myotubes with OA or LOA significantly enhanced Akt- and ERK1/2-directed insulin signalling. This was not due to heightened upstream IRS1 or PI3K signalling nor to changes in expression of proteins involved in proximal insulin signalling, but was associated with reduced dephosphorylation/inactivation of Akt and ERK1/2. Consistent with this, PA reduced PP2Ac demethylation and tyrosine307phosphorylation - events associated with PP2A activation. In contrast, OA and LOA strongly opposed these PA-induced changes in PP2Ac thus exerting a repressive effect on PP2A.Conclusions/InterpretationBeneficial gains in insulin sensitivity and the ability of unsaturated fatty acids to oppose palmitate-induced insulin resistance in muscle cells may partly be accounted for by counter-modulation of PP2A.
Highlights
Sustained elevation in circulating non-esterified free fatty acids (NEFA) as seen during obesity and Type 2 diabetes is associated with impaired insulin signalling in tissues such as skeletal muscle potentially contributing to disturbances in whole body glucose metabolism in obese or diabetic individuals [1,2,3]
This enhancement was significant at fatty acid concentrations as low as 200 mM and was,2-fold greater than that elicited by insulin treatment alone when myotubes were pre-exposed to maximally effective doses (700 mM) of oleic acid (OA) or linoleic acid (LOA) (Fig 1B, 1C)
Numerous studies have demonstrated that increased availability of saturated fatty acids (SFA) negatively regulate skeletal muscle insulin sensitivity with important knock-on consequences for processes such as gene expression and cell metabolism that are normally regulated by the hormone [8,33,34,35]
Summary
Sustained elevation in circulating non-esterified free fatty acids (NEFA) as seen during obesity and Type 2 diabetes is associated with impaired insulin signalling in tissues such as skeletal muscle potentially contributing to disturbances in whole body glucose metabolism in obese or diabetic individuals [1,2,3]. Dietary substitution of SFAs or co-supplementation with unsaturated fatty acids antagonise the insulin desensitising effects of SFAs, enhance energy expenditure and improve muscle lipid composition and serum acylcarnitine profiles in humans [10,11,12,13,14]. Such observations are in line with cell-based studies demonstrating that monounsaturated fatty acids (MUFAs), such as palmitoleate and oleate, attenuate the SFA-induced loss in mitochondrial integrity and function and repress their proinflammatory and ER stressinducing potential [15,16,17,18]. Despite the observed gain in insulin sensitivity brought about by palmitoleate in these peripheral tissues, our understanding of the underlying mechanism remains poor [19]
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