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The Rexinoid LG100754 Is a Novel RXR:PPARgamma Agonist and Decreases Glucose Levels in Vivo

The Rexinoid LG100754 Is a Novel RXR:PPARgamma Agonist and Decreases Glucose Levels in Vivo

R M Cesario, K Klausing, H Razzaghi, D Crombie, D Rungta, R A Heyman, D S Lala

Mol Endocrinol. 2001 Aug;15(8):1360-9.

PMID: 11463859

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP180713375	LG100754		180713-37-5	Price

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