Effects of pioglitazone and high-fat diet on ceramide metabolism in rat skeletal muscles.

Ceramide is involved in the pathogenesis of insulin resistance in skeletal muscles of humans and rodents. However, there are conflicting reports in the literature on the effect of thiazolidinediones (a new class of insulin sensitizing drugs) on skeletal muscle ceramide content. Therefore, the aim of our study was to examine the effect of pioglitazone on the level of ceramide and its metabolites and on the activity of the key enzymes of ceramide metabolism in different skeletal muscle types of the rat. The experiments were carried out on rats fed either a standard chow or a high-fat diet for 21 days. Each group was divided into two subgroups: control and treated with pioglitazone for 14 days. High-fat diet increased the content of ceramide in the soleus and in the red section of the gastrocnemius, but not in the white section of the latter. The activity of neutral Mg(2+)-dependent sphingomyelinase and acid sphingomyelinase was simultaneously reduced in all examined muscles. Administration of pioglitazone decreased ceramide level in the soleus and in the red section of the gastrocnemius in rats fed either diet. This effect could not be attributed to decreased rate of ceramide formation from sphingomyelin or to its augmented deacylation to sphingosine. Pioglitazone treatment reduced the concentration of plasma free fatty acids in rats fed on either diet. Therefore, we conclude that the drug decreased the muscle content of ceramide by reducing its de novo synthesis. The results of our study indicate that reduction in ceramide level may be one of the mechanisms by which pioglitazone improves skeletal muscle insulin sensitivity.