Submitted on May 7, 2009
Revised on September 2, 2009
Accepted on September 7, 2009
Different Impacts of Saturated and Unsaturated Free Fatty Acids on COX-2 Expression in C2C12 Myotubes
Akito Kadotani1, Yo Tsuchiya2, Hiroyasu Hatakeyama1, Hideki Katagiri1, and Makoto Kanzaki1*
1 Tohoku University
2 Kyoto Prefectural University of Medicine
* To whom correspondence should be addressed. E-mail: kanzaki{at}bme.tohoku.ac.jp.
In skeletal muscle, saturated free fatty acids (FFAs) act as pro-inflammatory 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], stearate [18:0]), but not to unsaturated FFAs (palmitoleate [16:1], oleate [18:1], 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 
-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 towards 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.
