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

Abstract

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.

• Authors: R M Cesario, K Klausing, H Razzaghi, D Crombie, D Rungta, R A Heyman, D S Lala
• Journal: Molecular endocrinology (Baltimore, Md.) (Mol Endocrinol) Vol. 15 Issue 8 Pg. 1360-9 (Aug 2001) ISSN: 0888-8809 [Print] United States
• PMID: 11463859 (Publication Type: Comparative Study, Journal Article)

Chemical References

• 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

Topics

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