Free fatty acid-induced muscle insulin resistance and glucose uptake dysfunction: Evidence for PKC activation and oxidative stress-activated signaling pathways

Abstract

In the present study, we examined the effects of free fatty acids (FFAs) on insulin sensitivity and signaling cascades in the C2C12 skeletal muscle cell culture system. Our data clearly manifested that the inhibitory effects of PKC on insulin signaling may at least in part be explained by the serine/threonine phosphorylation of IRS-1. Both oleate and palmitate treatment were able to increase the Serine 307 phosphorylation of IRS-1. IRS-1 Serine 307 phosphorylation is inducible which causes the inhibition of IRS-1 tyrosine phosphorylation by either IκB-kinase (IKK) or c-jun N-terminal kinase (JNK) as seen in our proteomic kinases screen. Furthermore, our proteomic data have also manifested that the two FFAs activate the IKKα/β, the stress kinases S6 kinase p70 (p70SK), stress-activated protein kinase (SAPK), JNK, as well as p38 MAP kinase (p38MAPK). On the other hand, the antioxidant, Taurine at 10 mM concentrations was capable of reversing the oleate-induced insulin resistance in myocytes as manifested from the glucose uptake data. Our current data point out the importance of FFA-induced insulin resistance via multiple signaling mechanisms. KeywordsFree fatty acid (FFA); Insulin resistance (IR); Skeletal muscle cell (C2C12); Protein kinase C (PKC); Insulin receptor substrate-1 (IRS-1)

The Effects of Palmitate on Hepatic Insulin Resistance Are Mediated by NADPH Oxidase 3-derived Reactive Oxygen Species through JNK and p38MAPK Pathways

“…However, it has been suggested that the effect on JNK and p38 MAPK pathways is not specific to palmitate. It can also arise from exposure to other long-and mediumchain fatty acids (41)(42)(43). Interestingly, others have demonstrated that a saturated fatty acid (palmitate) but not a monounsaturated fatty acid (oleate) inhibited insulin-stimulated tyrosine phosphorylation of IRS2 and serine phosphorylation of Akt through JNK activation in rat H4IIEC3 cells (9).…”

Phenylmethimazole blocks palmitate-mediated induction of inflammatory cytokine pathways in 3T3L1 adipocytes and RAW 264.7 macrophages

“…), which circulate via the portal and systemic vascular system to other insulin target tissues (liver, muscle and islet cells) and induce insulin resistance (Kahn & Flier 2000, Steppan et al 2001, Wellen & Hotamisligil 2003, Lau et al 2005. Excess saturated free fatty acids (FFAs) such as palmitate activate inflammation and induce insulin resistance via multiple mechanisms including, but not limited to, serine phosphorylation of insulin receptor substrate-1 (IRS-1) and up-regulation of suppressors of cytokine signaling (SOCS; Paz et al 1997, Lin et al 2000, Emanuelli et al 2001, Perreault & Marette 2001, Aguirre et al 2002, Chavez et al 2003, Furukawa et al 2004, Ajuwon & Spurlock 2005, Boden et al 2005, Hotamisligil 2005, Jove et al 2005, Khamzina et al 2005, Shi et al 2006, Solinas et al 2006, Nakamura et al 2009, Ragheb et al 2009). Therefore, agents capable of blocking FFA-mediated inflammation and insulin resistance may be useful as novel therapeutics for the treatment of T2DM.…”

Supplementation of pyruvate prevents palmitate-induced impairment of glucose uptake in C2 myotubes

“…FFA-induced activation of serine kinases was thought to be due to signal activation through different lipid intermediates such as ceramide, diacylglycerol, and lysophosphatidic acid, which are produced by an augmented lipogenic pathway (Boden et al, 1998). Oxidative stress or endoplasmic reticular stress is also a critical mediator of FFA-induced activation of stress-related serine kinases (Peter et al, 2009;Ragheb et al, 2009;Ye, 2007). Alternatively, prolonged treatment with FFA may interfere with glucose uptake by mechanisms that are independent of the insulin signaling pathway (Armoni et al, 2005a,b).…”