Different impacts of saturated and unsaturated free fatty acids on COX-2 expression in C(2)C(12) myotubes.
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 C(2)C(12) 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 E(2) production via mechanisms involving the p38 MAPK and NF-kappaB but not the PKC signaling cascades. Pharmacological modulation of mitochondrial oxidative function failed to interfere with COX-2 expression, suggesting the mitochondrial overload/excessive beta-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 PKCtheta, as well as IkappaB 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.
Kadotani
Akito
A
Center for Research Strategy and Support, Tohoku University, Aoba-ku, Sendai, Japan.
Tsuchiya
Yo
Y
Hatakeyama
Hiroyasu
H
Katagiri
Hideki
H
Kanzaki
Makoto
M
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism / Q000494:pharmacology*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D051379:Mice; D008931:Mitochondria, Muscle / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D005227:Fatty Acids; D005229:Fatty Acids, Monounsaturated; D005231:Fatty Acids, Unsaturated; D051275:Glucose Transporter Type 4; D016328:NF-kappa B; D012333:RNA, Messenger; C008757:palmitoleic acid; D051546:Cyclooxygenase 2; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D015232:Dinoprostone