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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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3T3 Cells
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Adipose Tissue / metabolism
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Animals
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Benzhydryl Compounds
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Benzoates / metabolism
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Benzoates / pharmacology
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Biphenyl Compounds / metabolism
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Biphenyl Compounds / pharmacology
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Diabetes Mellitus, Type 2 / metabolism*
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Epoxy Compounds / metabolism
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Epoxy Compounds / pharmacology
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Fatty Acids / metabolism
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Hyperglycemia / etiology
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Hyperglycemia / metabolism
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Hypoglycemic Agents / metabolism
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Hypoglycemic Agents / pharmacology
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Insulin Resistance
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Leptin / metabolism
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Mice
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Mice, Knockout
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Nicotinic Acids / metabolism
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Nicotinic Acids / pharmacology
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Obesity / metabolism*
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Receptors, Adrenergic, beta-3 / metabolism
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Receptors, Cytoplasmic and Nuclear / agonists
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Receptors, Cytoplasmic and Nuclear / antagonists & inhibitors*
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Receptors, Cytoplasmic and Nuclear / metabolism
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Receptors, Retinoic Acid / agonists
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Receptors, Retinoic Acid / antagonists & inhibitors*
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Receptors, Retinoic Acid / metabolism
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Retinoid X Receptors
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Rosiglitazone
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Tetrahydronaphthalenes / metabolism
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Tetrahydronaphthalenes / pharmacology
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Thiazoles / metabolism
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Thiazoles / pharmacology
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Thiazolidinediones*
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Transcription Factors / agonists
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / metabolism
Substances
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Benzhydryl Compounds
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Benzoates
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Biphenyl Compounds
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Epoxy Compounds
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Fatty Acids
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Hypoglycemic Agents
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Leptin
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Nicotinic Acids
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Receptors, Adrenergic, beta-3
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Retinoid X Receptors
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Tetrahydronaphthalenes
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Thiazoles
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Thiazolidinediones
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Transcription Factors
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diazepinylbenzoic acid
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Rosiglitazone
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2,2-bis(4-glycidyloxyphenyl)propane
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LG 100268