The rexinoid LG100754 is a novel RXR:PPARgamma agonist and decreases glucose levels in vivo

Mol Endocrinol. 2001 Aug;15(8):1360-9. doi: 10.1210/mend.15.8.0677.


The RXR serves as a heterodimer partner for the PPARgamma and the dimer is a molecular target for insulin sensitizers such as the thiazolidinediones. Ligands for either receptor can activate PPAR-dependent pathways via PPAR response elements. Unlike PPARgamma agonists, however, RXR agonists like LG100268 are promiscuous and activate multiple RXR heterodimers. Here, we demonstrate that LG100754, a RXR:RXR antagonist and RXR:PPARalpha agonist, also functions as a RXR:PPARgamma agonist. It does not activate other LG100268 responsive heterodimers like RXR:liver X receptoralpha, RXR:liver X receptorbeta, RXR:bile acid receptor/farnesoid X receptor and RXR:nerve growth factor induced gene B. This unique RXR ligand triggers cellular RXR:PPARgamma-dependent pathways including adipocyte differentiation and inhibition of TNFalpha-mediated hypophosphorylation of the insulin receptor, but does not activate key farnesoid X receptor and liver X receptor target genes. Also, LG100754 treatment of db/db animals leads to an improvement in insulin resistance in vivo. Interestingly, activation of RXR:PPARgamma by LG100268 and LG100754 occurs through different mechanisms. Therefore, LG100754 represents a novel class of insulin sensitizers that functions through RXR but exhibits greater heterodimer selectivity compared with LG100268. These results establish an approach to the design of novel RXR-based insulin sensitizers with greater specificity.

Publication types

  • Comparative Study

MeSH terms

  • 3T3 Cells
  • Adipocytes / drug effects
  • Adipocytes / metabolism
  • Animals
  • Blood Glucose / metabolism*
  • Cell Differentiation / drug effects
  • Diabetes Mellitus / blood
  • Diabetes Mellitus / drug therapy
  • Dimerization
  • Insulin Resistance
  • Mice
  • Nicotinic Acids / pharmacology
  • Phosphorylation
  • Receptor, Insulin / metabolism
  • Receptors, Cytoplasmic and Nuclear / agonists*
  • Receptors, Cytoplasmic and Nuclear / drug effects
  • Receptors, Cytoplasmic and Nuclear / physiology
  • Receptors, Retinoic Acid / agonists*
  • Receptors, Retinoic Acid / drug effects
  • Receptors, Retinoic Acid / physiology
  • Retinoid X Receptors
  • Retinoids / pharmacology*
  • Retinoids / therapeutic use
  • Tetrahydronaphthalenes / pharmacology*
  • Tetrahydronaphthalenes / therapeutic use
  • Transcription Factors / agonists*
  • Transcription Factors / drug effects
  • Transcription Factors / physiology
  • Tumor Necrosis Factor-alpha / pharmacology


  • Blood Glucose
  • LG 100754
  • Nicotinic Acids
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Retinoid X Receptors
  • Retinoids
  • Tetrahydronaphthalenes
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Receptor, Insulin
  • LG 100268