Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes
| Autor: | Kiyoto Motojima, Junji Kamon, Akiko Itai, Koichi Shudo, Hiroyuki Kagechika, Hironori Waki, Nobuyo Tsuboyama-Kasaoka, Shigeaki Kato, Hiroshi Miki, Ryozo Nagai, Koji Murakami, Masashi Fukayama, Kajuro Komeda, Yasuo Terauchi, Naoko Yamauchi, Yasuo Akanuma, Kazuyuki Tobe, Tomohiro Ide, Toshimasa Yamauchi, Naoto Kubota, Takashi Kadowaki, Osamu Ezaki, Atsuko Tsuchida, Wataru Hori, Satoshi Kimura |
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| Rok vydání: | 2001 |
| Předmět: |
Leptin
medicine.medical_specialty Tetrahydronaphthalenes Receptors Retinoic Acid Receptors Cytoplasmic and Nuclear Adipose tissue Peroxisome proliferator-activated receptor White adipose tissue Type 2 diabetes Biology Benzoates Article Rosiglitazone Mice Insulin resistance Internal medicine Diabetes mellitus medicine Animals Hypoglycemic Agents Obesity Benzhydryl Compounds Mice Knockout chemistry.chemical_classification Biphenyl Compounds Fatty Acids Nicotinic Acids 3T3 Cells General Medicine medicine.disease Thiazoles Retinoid X Receptors Endocrinology Adipose Tissue Diabetes Mellitus Type 2 chemistry Hyperglycemia Receptors Adrenergic beta-3 Epoxy Compounds Thiazolidinediones Insulin Resistance Transcription Factors medicine.drug |
| Zdroj: | Journal of Clinical Investigation. 108:1001-1013 |
| ISSN: | 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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