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This Article Full Text Full Text (PDF) All Versions of this Article: 297/6/E1291    most recent 00293.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kadotani, A. Articles by Kanzaki, M. PubMed PubMed Citation Articles by Kadotani, A. Articles by Kanzaki, M.

Different impacts of saturated and unsaturated free fatty acids on COX-2 expression in C₂C₁₂ myotubes

¹Center for Research Strategy and Support; ²Division of Advanced Therapeutics for Metabolic Diseases, Center for Translational and Advanced Animal Research; ³Graduate School of Biomedical Engineering, Tohoku University, Sendai and ⁴Japan Science and Technology Agency, Core Research for Evolutionary Science and Technology, Tokyo, Japan

Submitted 7 May 2009 ; accepted in final form 7 September 2009

In skeletal muscle, saturated free fatty acids (FFAs) act as proinflammatory stimuli, and cyclooxygenase-2 (COX-2) is a pro/anti-inflammatory enzyme induced at sites of inflammation, which contributes to prostaglandin production. However, little is known about the regulation of COX-2 expression and its responses to FFAs in skeletal muscle. Herein, we examined the effects of saturated and unsaturated FFAs, including a recently identified lipokine (lipid hormone derived from adipocytes), palmitoleate, on COX-2 expression in C₂C₁₂ myotubes as a skeletal muscle model. Exposure of myotubes to saturated FFAs [palmitate (16:0) and stearate (18:0)], but not to unsaturated FFAs [palmitoleate (16:1), oleate (18:1), and linoleate (18:2)], led to a slow-onset induction of COX-2 expression and subsequent prostaglandin E₂ production via mechanisms involving the p38 MAPK and NF-B but not the PKC signaling cascades. Pharmacological modulation of mitochondrial oxidative function failed to interfere with COX-2 expression, suggesting the mitochondrial overload/excessive β-oxidation contribution to this event to be minimal. On the contrary, unsaturated FFAs appeared to effectively antagonize palmitate-induced COX-2 expression with markedly different potencies (linoleate > oleate > palmitoleate), being highly associated with the suppressive profile of each unsaturated FFA toward palmitate-evoked intracellular signals, including p38, JNK, ERK1/2 MAPKs, and PKC, as well as IB degradation. In addition, our data suggest little involvement of PPAR in the protective actions of unsaturated FFAs against palmitate-induced COX-2 expression. No direct contribution of the increased COX-2 activity in generating palmitate-induced insulin resistance was detected, at least in terms of insulin-responsive Akt phosphorylation and GLUT4 translocation. Taken together, our data provide a novel insight into the molecular mechanisms responsible for the FFA-induced COX-2 expression in skeletal muscle and raise the possibility that, in skeletal myocytes, COX-2 and its product prostaglandins may play an important role in the complex inflammation responses caused by elevated FFAs, for example, in the diabetic state.

cyclooxygenase-2; inflammation; signal transduction; glucose transporter 4; insulin resistance