Differential Effects of Rexinoids and Thiazolidinediones on Metabolic Gene Expression in Diabetic Rodents

  1. Harleen Singh Ahuja1,
  2. Sha Liu3,
  3. Diane L. Crombie3,
  4. Marcus Boehm3,
  5. Mark D. Leibowitz3,
  6. Richard A. Heyman3,
  7. Christophe Depre2,
  8. Laszlo Nagy4,
  9. Peter Tontonoz4 and
  10. Peter J. A. Davies1
  1. Departments of 1Integrative Biology and Pharmacology (H.S.A., P.J.A.D.) and 2Cardiology (C.D.), University of Texas Medical School, Houston, Texas; 3Ligand Pharmaceuticals, San Diego, California (S.L., D.L.C., M.B., M.D.L., R.A.H.); 4and The Salk Institute for Biological Studies, La Jolla, California (L.N., P.T.)

    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

    • 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

    • 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.

    • Abbreviations:
      TZD
      thiazolidinedione
      PPAR
      peroxisome proliferator-activated receptor
      TNF-α
      tumor necrosis factor-α
      GLUT4
      glucose transporter 4
      RXR
      retinoid X receptor
      OGTT
      oral glucose tolerance test
      AUC
      area under the curve
      ZDF
      Zucker diabetic fatty rat
      PCR
      polymerase chain reaction
      dNTP
      deoxynucleotide triphosphates
      RT
      reverse transcriptase
      MCPT
      muscle carnitine palmitoyl transferase
      SCD1
      stearoyl coenzyme A desaturase 1
      CD36
      fatty acid translocase
      CoA
      coenzyme A
      ANOVA
      analysis of variance
      • Received August 18, 2000.
      • Accepted August 18, 2000.
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    1. Molecular Pharmacology April 1, 2001 vol. 59 no. 4 765-773
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