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

Department of Nuclear Receptor Research (R.M.C., K.K., H.R., D.C., R.A.H., D.S.L.) and New Leads (D.R.), Ligand Pharmaceuticals, Inc., San Diego, California 92121

Address all correspondence and request for reprints to: Dr. Deepak S. Lala, Department of Biochemistry and Molecular Biology, Pharmacia Corporation, 700 Chesterfield Parkway North, St. Louis, Missouri 63198.

The RXR serves as a heterodimer partner for the PPAR 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 PPAR agonists, however, RXR agonists like LG100268 are promiscuous and activate multiple RXR heterodimers. Here, we demonstrate that LG100754, a RXR:RXR antagonist and RXR:PPAR agonist, also functions as a RXR:PPAR agonist. It does not activate other LG100268 responsive heterodimers like RXR:liver X receptor, RXR:liver X receptorß, RXR:bile acid receptor/farnesoid X receptor and RXR:nerve growth factor induced gene B. This unique RXR ligand triggers cellular RXR:PPAR-dependent pathways including adipocyte differentiation and inhibition of TNF-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:PPAR 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.

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