Differential effects of rexinoids and thiazolidinediones on metabolic geneexpression in diabetic rodents

Both retinoid X receptor (RXR)-selective agonists (rexinoids) and thiazolid inediones (TZDs), PPAR (peroxisome proliferator-activated receptor)-gamma - specific ligands, produce insulin sensitization in diabetic rodents. In vit ro studies have demonstrated that TZDs mediate their effects via the RXR/PP AR-gamma complex. To determine whether rexinoids lower hyperglycemia by act ivating the RXR/PPAR-gamma heterodimer in vivo, we compared the effects of a rexinoid (LG100268) and a TZD (rosiglitazone) on gene expression in white adipose tissue, skeletal muscle, and liver of Zucker diabetic fatty rats ( ZDFs). In adipose tissue, rosiglitazone decreased tumor necrosis factor-alp ha (TNF-alpha) mRNA and induced glucose transporter 4 (GLUT4), muscle carni tine palmitoyl-transferase (MCPT), stearoyl CoA desaturase (SCD1), and fatt y acid translocase (CD36). In contrast, LG100268 increased TNF-alpha and ha d no effect or suppressed the expression of GLUT4, MCPT, SCD1, and CD36. In liver, the rexinoid increased MCPT, SCD1, and CD36 mRNAs, whereas rosiglit azone induced only a small increase in CD36. In skeletal muscle, rosiglitaz one and LG100268 have similar effects; both increased SCD1 and CD36 mRNAs. The differences in the pattern of genes induced by the rexinoids and the TZ Ds in diabetic animals found in these studies suggests that these compounds may have independent and tissue-specific effects on metabolic control in v ivo.