Figure 1.

Mechanism linking excess fatty acids to insulin resistance in skeletal muscle. (A): (1) Excess free fatty acids (FFAs) are esterified in AcylCoAs, substrates involved in both synthetic and oxidative pathways. In the synthetic pathway, they are either stored as Triacylglycerols (TG) in lipid droplets or accumulated in metabolites (DAGs, Ceramides) that act as signaling molecules and may interfere with normal cellular signaling. DAGs are associated with membrane translocation and activation of Protein kinase C theta (PKC-θ), increased IRS1 serine/threonine phosphorylation and decreased insulin-stimulated IRS1 tyrosine phosphorylation, whereas Ceramides impair insulin action by inhibiting protein kinase PKB/AKT (dark blue). In the oxidative pathway, AcylCoAs are imported into the mitochondria by carnitine palmitoyltransferase-1 (CPT-1) shuttle and degraded via β-oxidation (in purple). (2) Insulin signaling pathway impaired by excess FFA (in green). Among FFAs, saturated FAs (SFAs) stimulate the activation of several inflammatory pathways. (3) Receptor-mediated mechanisms, as those of Toll like receptors 2/4 (TLR 2/4), activate serine kinases inhibitor kappaB kinase (IKK) and c-JUN NH₂-terminal kinase (JNK). The activation of PKCθ also contributes to IKK and JNK activation. Altogether, these kinases catalyze IRS1 serine phosphorylation and lead to a reduction of insulin-induced IRS1 tyrosine phosphorylation, impairing insulin action. Moreover, IKK/NFkB axis (4) triggers expression of inflammatory genes with cytokines production (e.g., Tumor necrosis factor, TNFα), which in turn activate intracellular pathways promoting insulin resistance development (in light blue). (5) SFAs enter the cellular membranes and incorporate into them reducing membrane fluidity and creating or expanding subdomains rich in cholesterol and sphingolipids (lipid raft). They induce clustering and activation of cytosolic cSRC. cSRC activity is required for JNK1 activation and inhibition of insulin signaling (in grey). (6) Endoplasmic reticulum stress (ER stress), induced by lipotoxicity, contributes to activate inflammatory pathways and impair insulin signaling. (B): Putative role of mitochondria in development of IR. Mitochondrial dysfunction in presence of excess FFAs leads to intramyocellular lipid accumulation due to impaired β-oxidation. Decreased mitochondrial mass, respiratory capacities and ATP synthesis have been found in obesity and diabetes. Alternatively, excess FFA within mitochondria in the absence of increased energy demand stimulates oxidative stress with high rates of ROS production and H₂O₂ emission and a shift to a more oxidized intracellular redox environment, ultimately leading to the development of IR.