lg100754 and Insulin-Resistance

Insulin resistance and non-insulin-dependent diabetes mellitus are major causes of morbidity and mortality in industrialized nations. Despite the alarming rise in the prevalence of this disorder, the initial molecular events that promote insulin resistance remain unclear. The data presented here demonstrate that LG100754, an antidiabetic RXR ligand, defines a novel type of nuclear receptor agonist. Surprisingly, LG100754 has minimal intrinsic transcriptional activity, instead it enhances the potency of proliferator-activated receptor (PPAR) gamma-retinoid X receptor heterodimers for PPARgamma ligands. The ability of LG100754 to both increase PPARgamma sensitivity and relieve insulin resistance implies that a deficiency in endogenous PPARgamma ligands may represent an early step in the development of insulin resistance.

Topics: Animals; Base Sequence; Diabetes Mellitus, Type 2; DNA Probes; Hypoglycemic Agents; Insulin Resistance; Ligands; Rats; Receptors, Cytoplasmic and Nuclear; Retinoids; Tetrahydronaphthalenes; Transcription Factors

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.

Topics: 3T3 Cells; Adipocytes; Animals; Blood Glucose; Cell Differentiation; Diabetes Mellitus; Dimerization; Insulin Resistance; Mice; Nicotinic Acids; Phosphorylation; Receptor, Insulin; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid; Retinoid X Receptors; Retinoids; Tetrahydronaphthalenes; Transcription Factors; Tumor Necrosis Factor-alpha