IN-VIVO EFFECTS OF PIOGLITAZONE ON UNCOUPLING PROTEIN-2 AND PROTEIN-3MESSENGER-RNA LEVELS IN SKELETAL-MUSCLE OF HYPERGLYCEMIC KK MICE

Pioglitazone is a thiazolidinedione drug (TZD) which potently and spec ifically stimulates peroxisome proliferator-activated receptor gamma ( PPAR gamma) and sensitizes cells to insulin. Since TZDs are thought to increase energy expenditure, changes in mitochondrial thermogenesis u ncoupling protein-2 and -3 mRNA levels in response to pioglitazone tre atment were measured in mouse skeletal muscle. Normally hyperglycemic and hyperinsulinemic KK/Ta mice were given pioglitazone for 2 weeks to treat this non-insulin dependent diabetes-like condition. During trea tment, UCP2 mRNA levels increased to 185% of normal untreated control levels in soleus muscle. In contrast, UCP3 mRNA levels significantly d ecreased, up to 67% of normal untreated control levels. Interestingly, UCP3 mRNA levels correlated quite strongly with blood glucose levels, with r = 0.82 for gastrocnemius tissue and r = 0.92 for soleus tissue . These results may indicate that pioglitazone increases glucose catab olism by direct upregulation of muscle UCP2 gene expression in vivo. T herefore, UCP3 gene expression is controlled by a different mechanism than UCP2 expression, (C) 1998 Academic Press.