Direct thiazolidinedione action on isolated rat skeletal muscle fuel handling is independent of peroxisome proliferator-activated receptor-gamma-mediated changes in gene expression

Thiazolidinediones (TZDs) are believed to induce insulin sensitization by m odulating gene expression via agonistic stimulation of the nuclear peroxiso me proliferator-activated receptor-gamma (PPAR-gamma). We have shown earlie r that the TZD troglitazone inhibits mitochondrial fuel oxidation in isolat ed rat skeletal muscle. In the present study, rat soleus muscle strips were exposed to TZDs to examine whether the inhibition of fuel oxidation is med iated by PPAR-gamma activation. Our findings consistently indicated direct, acute, and PPAR-gamma -independent TZD action on skeletal muscle fuel meta bolism. Rapid stimulation of lactate release by 20 mu mol/l troglitazone wi thin 30 min suggested that direct TZD action on skeletal muscle in vitro do es not rely on changes in gene expression rates (12.6 +/- 0.6 [control] vs. 16.0 +/- 0.8 mu mol . g(-1) . h(-1) [troglitazone]; P < 0.01). This conclu sion was supported by the failure of actinomycin D and cycloheximide to blo ck the effects of troglitazone. Mitochondrial fuel oxidation was consistent ly inhibited by six different TZDs (percent inhibition of CO2 production fr om palmitate after 25 h: troglitazone, -61 +/- 2%; pioglitazone, -43 +/- 7% ; rosiglitazone, -22 +/- 6%; BM13.1258, -47 +/- 9%; BM15.2054, -51 +/- 4%; and T-174, -59 +/- 4% [P < 0.005 each]), but not by PPAR-gamma agonistic co mpounds not belonging to the TZD class (JTT-501, -5 +/- 7% [NS]; prostaglan din J(2), 17 +/- 7% [P < 0.05]), which further argues against dependence on PPAR-<gamma> activation. In summary, our findings provided good evidence t hat direct inhibition of mitochondrial fuel oxidation in isolated skeletal muscle is a group-gamma -specific effect of TZDs and is independent of PPAR -gamma -mediated gene expression.