title: Biological characterization of a heterodimer-selective retinoid X receptor modulator: potential benefits for the treatment of type 2 diabetes.
abstract: Specific retinoid X receptor (RXR) agonists, such as LG100268 (LG268), and the thiazolidinedione (TZD) PPARgamma agonists, such as rosiglitazone, produce insulin sensitization in rodent models of insulin resistance and type 2 diabetes. In sharp contrast to the TZDs that produce significant increases in body weight gain, RXR agonists reduce body weight gain and food consumption. Unfortunately, RXR agonists also suppress the thyroid hormone axis and generally produce hypertriglyceridemia. Heterodimer-selective RXR modulators have been identified that, in rodents, retain the metabolic benefits of RXR agonists with reduced side effects. These modulators bind specifically to RXR with high affinity and are RXR homodimer partial agonists. Although RXR agonists activate many heterodimer partners, these modulators selectively activate RXR:PPARalpha and RXR:PPARgamma, but not RXR:RARalpha, RXR:LXRalpha, RXR:LXRbeta, or RXR:FXRalpha. We report the in vivo characterization of one RXR modulator, LG101506 (LG1506). In Zucker fatty (fa/fa) rats, LG1506 is a potent insulin sensitizer that also enhances the insulin-sensitizing activities of rosiglitazone. Administration of LG1506 reduces both body weight gain and food consumption and blocks the TZD-induced weight gain when coadministered with rosiglitazone. LG1506 does not significantly suppress the thyroid hormone axis in rats, nor does it elevate triglycerides in Sprague Dawley rats. However, LG1506 produces a unique pattern of triglycerides elevation in Zucker rats. LG1506 elevates high-density lipoprotein cholesterol in humanized apolipoprotein A-1-transgenic mice. Therefore, selective RXR modulators are a promising approach for developing improved therapies for type 2 diabetes, although additional studies are needed to understand the strain-specific effects on triglycerides.
authors.affiliation: Ligand Pharmaceuticals, Inc., San Diego, California 92121, USA. mleibowitz@ligand.com
authors.forename: Mark D
authors.initials: MD
authors.lastname: Leibowitz
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Ardecky
authors.forename: Marcus F
authors.initials: MF
authors.lastname: Boehm
authors.forename: Carol L
authors.initials: CL
authors.lastname: Broderick
authors.forename: Mark A
authors.initials: MA
authors.lastname: Carfagna
authors.forename: Diane L
authors.initials: DL
authors.lastname: Crombie
authors.forename: Jennifer
authors.initials: J
authors.lastname: D'Arrigo
authors.forename: Garrett J
authors.initials: GJ
authors.lastname: Etgen
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Faul
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Grese
authors.forename: Henry
authors.initials: H
authors.lastname: Havel
authors.forename: Nancy I
authors.initials: NI
authors.lastname: Hein
authors.forename: Richard A
authors.initials: RA
authors.lastname: Heyman
authors.forename: Diane
authors.initials: D
authors.lastname: Jolley
authors.forename: Kay
authors.initials: K
authors.lastname: Klausing
authors.forename: Sha
authors.initials: S
authors.lastname: Liu
authors.forename: Dale E
authors.initials: DE
authors.lastname: Mais
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Mapes
authors.forename: Keith B
authors.initials: KB
authors.lastname: Marschke
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Michellys
authors.forename: Chahrzad
authors.initials: C
authors.lastname: Montrose-Rafizadeh
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Ogilvie
authors.forename: Bernadette
authors.initials: B
authors.lastname: Pascual
authors.forename: Deepa
authors.initials: D
authors.lastname: Rungta
authors.forename: John S
authors.initials: JS
authors.lastname: Tyhonas
authors.forename: Mary S
authors.initials: MS
authors.lastname: Urcan
authors.forename: Marilyn
authors.initials: M
authors.lastname: Wardlow
authors.forename: Nathan
authors.initials: N
authors.lastname: Yumibe
authors.forename: Anne
authors.initials: A
authors.lastname: Reifel-Miller
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics / Q000502:physiology; D019540:Area Under Curve; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage*; D005260:Female; D007004:Hypoglycemic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D010647:Phenyl Ethers / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D047488:Retinoid X Receptors / Q000819:agonists* / Q000378:metabolism; D000077154:Rosiglitazone; D018709:Statistics, Nonparametric; D045162:Thiazolidinediones / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D013961:Thyroid Gland / Q000187:drug effects; D014280:Triglycerides / Q000097:blood
chemical_list: C508470:7-(2-(2,2-difluoroethoxy)-3,5-di-tert-butylbenzene)-3-methylocta-2,4,6-trienoic acid; D016632:Apolipoprotein A-I; D005231:Fatty Acids, Unsaturated; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D010647:Phenyl Ethers; D047488:Retinoid X Receptors; D045162:Thiazolidinediones; D014280:Triglycerides; D000077154:Rosiglitazone