RT Journal Article
SR Electronic
T1 Differential Effects of Rexinoids and Thiazolidinediones on Metabolic Gene Expression in Diabetic Rodents
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 765
OP 773
DO 10.1124/mol.59.4.765
VO 59
IS 4
A1 Ahuja, Harleen Singh
A1 Liu, Sha
A1 Crombie, Diane L.
A1 Boehm, Marcus
A1 Leibowitz, Mark D.
A1 Heyman, Richard A.
A1 Depre, Christophe
A1 Nagy, Laszlo
A1 Tontonoz, Peter
A1 Davies, Peter J. A.
YR 2001
UL http://molpharm.aspetjournals.org/content/59/4/765.abstract
AB Both retinoid X receptor (RXR)-selective agonists (rexinoids) and thiazolidinediones (TZDs), PPAR (peroxisome proliferator-activated receptor)-γ–specific ligands, produce insulin sensitization in diabetic rodents. In vitro studies have demonstrated that TZDs mediate their effects via the RXR/PPAR-γ complex. To determine whether rexinoids lower hyperglycemia by activating the RXR/PPAR-γ 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-α (TNF-α) mRNA and induced glucose transporter 4 (GLUT4), muscle carnitine palmitoyl-transferase (MCPT), stearoyl CoA desaturase (SCD1), and fatty acid translocase (CD36). In contrast, LG100268 increased TNF-α and had no effect or suppressed the expression of GLUT4, MCPT, SCD1, and CD36. In liver, the rexinoid increased MCPT, SCD1, and CD36 mRNAs, whereas rosiglitazone induced only a small increase in CD36. In skeletal muscle, rosiglitazone and LG100268 have similar effects; both increased SCD1 and CD36 mRNAs. The differences in the pattern of genes induced by the rexinoids and the TZDs in diabetic animals found in these studies suggests that these compounds may have independent and tissue-specific effects on metabolic control in vivo.