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Inhibition of RXR and PPARgamma ameliorates diet-induced obesity and type 2 diabetes.
| Content Provider | Semantic Scholar |
|---|---|
| Author | Yamauchi, Tatsuyuki Waki, Hironori Kamon, Junji Murakami, Koji Motojima, Kiyoto Komeda, Kajuro Miki, Hiroaki Kubota, Naoto Terauchi, Yasuo Tsuchida, Atsushi Tsuboyama-Kasaoka, Nobuyo Yamauchi, Naoko Ide, Tomomi Hori, Wataru Kato, Shigeaki Fukayama, Masashi Akanuma, Yasuo Ezaki, Osamu Itai, Akiko Nagai, Ryozo Kimura, Satoshi Kensuke Tobe, Kazuyuki Kagechika, Hiroyuki Shudo, Koichi Kadowaki, Takashi |
| Copyright Year | 2001 |
| 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. |
| Starting Page | 53 |
| Ending Page | 60 |
| Page Count | 8 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://dm5migu4zj3pb.cloudfront.net/manuscripts/12000/12864/JCI0112864.pdf |
| PubMed reference number | 11581301v1 |
| Volume Number | 108 |
| Issue Number | 7 |
| Journal | The Journal of clinical investigation |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | Diabetes Mellitus Diabetes Mellitus, Non-Insulin-Dependent Diet, High-Fat Fatty Acids Heparin, Low-Molecular-Weight Hyperglycemia Insulin Resistance Obesity PPAR gamma PPARG wt Allele Retinoid X Receptors Retinoids Skeletal muscle structure TRANSCRIPTION FACTOR Thiazolidinediones Triglycerides White Adipose Tissue leptin ligands activity |
| Content Type | Text |
| Resource Type | Article |
