Abstract
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.
Footnotes
- Received August 18, 2000.
- Accepted August 18, 2000.
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Send reprint requests to: Dr. Peter J. A. Davies, Department of Integrative Biology and Pharmacology, University of Texas at Houston School of Medicine, Houston, TX 77030. E-mail:peter.j.davies{at}uth.tmc.edu
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These studies were supported in part by a sponsored research agreement between Ligand Pharmaceuticals and the University of Texas Houston Health Science Center. H.S.A. is supported by a grant from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases and (5F32-DK09659–02) and L.N. was supported by a Boehringer Ingelheim research award.
- The American Society for Pharmacology and Experimental Therapeutics
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