Palmitate-induced skeletal muscle insulin resistance does not require NF-κB activation.

Palmitate activates the NF-κB pathway, and induces accumulation of lipid metabolites and insulin resistance in skeletal muscle cells. Little information is available whether and how these processes are causally related. Therefore, the objectives were to investigate whether intra-cellular lipid metabolites are involved in FA-induced NF-κB activation and/or insulin resistance in skeletal muscle and to investigate whether FA-induced insulin resistance and NF-κB activation are causally related. Inhibiting DGAT or CPT-1 by using, respectively, amidepsine or etomoxir increased DAG accumulation and sensitized myotubes to palmitate-induced insulin resistance. While co-incubation of palmitate with etomoxir increased NF-κB transactivation, co-incubation with amidepsine did not, indicating that DAG accumulation is associated with insulin resistance but not with NF-κB activation. Furthermore, pharmacological or genetic inhibition of the NF-κB pathway could not prevent palmitate-induced insulin resistance. In conclusion, we have demonstrated that activation of the NF-κB pathway is not required for palmitate-induced insulin resistance in skeletal muscle cells.

Trans fatty acid-induced NF-kappaB activation does not induce insulin resistance in cultured murine skeletal muscle cells.

Long-chain saturated fatty acids such as palmitic acid induce insulin resistance and NF-kappaB activation in skeletal muscle cells. Here we investigated the effects of long-chain fatty acid (FA) saturation and configuration on NF-kappaB activity and insulin sensitivity in cultured skeletal muscle cells. Of all tested unsaturated FAs, only elaidic acid (3-fold), cis9,trans11-CLA (3-fold) and trans10,cis12-CLA (13-fold) increased NF-kappaB transactivation in myotubes. This was not accompanied by decreased insulin sensitivity (measured as insulin-induced glucose uptake and GLUT4 translocation). We therefore conclude that FA-induced NF-kappaB activation is not sufficient for the induction of insulin resistance in skeletal muscle cells.

Trans-10, cis-12 conjugated linoleic acid inhibits skeletal muscle differentiation and GLUT4 expression independently from NF-κB activation.

SCOPE: The capacity of skeletal muscle to contribute to glucose homeostasis depends on muscular insulin sensitivity. The expression of glucose transporter (GLUT)-4 is increased during myoblast differentiation, a process essential in maintenance of adult muscle. Therefore, processes that affect muscle differentiation may influence insulin dependent glucose homeostasis. Conjugated linoleic acids, and in particular trans-10, cis-12 CLA (t10, c12-CLA), are potent inducers of NF-kB in cultured skeletal myotubes, and NF-kB activation inhibits muscle differentiation. The aims of this study were to evaluate whether CLAs inhibit myogenic differentiation and lower GLUT4 mRNA expression and to address the involvement of NF-kB activation in potential effects of CLA on these processes. METHODS AND RESULTS: Incubation of C2C12 cells with t10, c12-CLA blocked the formation of myotubes, which was accompanied by reduced expression of the muscle specific genes creatine kinase, myogenin, myosin heavy chain perinatal and myosin heavy chain IIB, as well as decreased GLUT4 mRNA levels. However, genetic blockade of NF-kB was not sufficient to restore reduced myosin heavy chain protein expression following t10, c12-CLA treatment. Surprisingly, in contrast to myotubes, t10, c12-CLA was not able to activate NF-kB transcriptional activity in myoblasts. CONCLUSION: In conclusion, t10, c12-CLA inhibits myogenic differentiation and GLUT4 expression, independently from NF-kB activation.