title: Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes.
abstract: PPARgamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARgamma by thiazolidinediones can reduce insulin resistance and hyperglycemia in type 2 diabetes, but these drugs can also cause weight gain. Quite unexpectedly, a moderate reduction of PPARgamma activity observed in heterozygous PPARgamma-deficient mice or the Pro12Ala polymorphism in human PPARgamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARgamma/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARgamma antagonist decrease triglyceride (TG) content in white adipose tissue, skeletal muscle, and liver. These inhibitors potentiated leptin's effects and increased fatty acid combustion and energy dissipation, thereby ameliorating HF diet-induced obesity and insulin resistance. Paradoxically, treatment of heterozygous PPARgamma-deficient mice with an RXR antagonist or a PPARgamma antagonist depletes white adipose tissue and markedly decreases leptin levels and energy dissipation, which increases TG content in skeletal muscle and the liver, thereby leading to the re-emergence of insulin resistance. Our data suggested that appropriate functional antagonism of PPARgamma/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.
authors.affiliation: Department of Internal Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yamauchi
authors.forename: H
authors.initials: H
authors.lastname: Waki
authors.forename: J
authors.initials: J
authors.lastname: Kamon
authors.forename: K
authors.initials: K
authors.lastname: Murakami
authors.forename: K
authors.initials: K
authors.lastname: Motojima
authors.forename: K
authors.initials: K
authors.lastname: Komeda
authors.forename: H
authors.initials: H
authors.lastname: Miki
authors.forename: N
authors.initials: N
authors.lastname: Kubota
authors.forename: Y
authors.initials: Y
authors.lastname: Terauchi
authors.forename: A
authors.initials: A
authors.lastname: Tsuchida
authors.forename: N
authors.initials: N
authors.lastname: Tsuboyama-Kasaoka
authors.forename: N
authors.initials: N
authors.lastname: Yamauchi
authors.forename: T
authors.initials: T
authors.lastname: Ide
authors.forename: W
authors.initials: W
authors.lastname: Hori
authors.forename: S
authors.initials: S
authors.lastname: Kato
authors.forename: M
authors.initials: M
authors.lastname: Fukayama
authors.forename: Y
authors.initials: Y
authors.lastname: Akanuma
authors.forename: O
authors.initials: O
authors.lastname: Ezaki
authors.forename: A
authors.initials: A
authors.lastname: Itai
authors.forename: R
authors.initials: R
authors.lastname: Nagai
authors.forename: S
authors.initials: S
authors.lastname: Kimura
authors.forename: K
authors.initials: K
authors.lastname: Tobe
authors.forename: H
authors.initials: H
authors.lastname: Kagechika
authors.forename: K
authors.initials: K
authors.lastname: Shudo
authors.forename: T
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D016475:3T3 Cells; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001559:Benzhydryl Compounds; D001565:Benzoates / Q000378:metabolism / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009539:Nicotinic Acids / Q000378:metabolism / Q000494:pharmacology; D009765:Obesity / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047488:Retinoid X Receptors; D000077154:Rosiglitazone; D013764:Tetrahydronaphthalenes / Q000378:metabolism / Q000494:pharmacology; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D001565:Benzoates; D001713:Biphenyl Compounds; D004852:Epoxy Compounds; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D020738:Leptin; D009539:Nicotinic Acids; D022702:Receptors, Adrenergic, beta-3; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D000077154:Rosiglitazone; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; C438269:diazepinylbenzoic acid; C019273:bisphenol A diglycidyl ether; D000098826:Bisphenol A Compounds; C095104:LG 100268