title: 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.affiliation: Department of Nuclear Receptor Research, Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Cesario
authors.forename: K
authors.initials: K
authors.lastname: Klausing
authors.forename: H
authors.initials: H
authors.lastname: Razzaghi
authors.forename: D
authors.initials: D
authors.lastname: Crombie
authors.forename: D
authors.initials: D
authors.lastname: Rungta
authors.forename: R A
authors.initials: RA
authors.lastname: Heyman
authors.forename: D S
authors.initials: DS
authors.lastname: Lala
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy; D019281:Dimerization; D007333:Insulin Resistance; D051379:Mice; D009539:Nicotinic Acids / Q000494:pharmacology; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000187:drug effects / Q000502:physiology; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000187:drug effects / Q000502:physiology; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology* / Q000627:therapeutic use; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000819:agonists* / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; C101596:LG 100754; D009539:Nicotinic Acids; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D011972:Receptor, Insulin; C095104:LG 100268