Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes
Toshimasa Yamauchi, Hironori Waki, Junji Kamon, Koji Murakami, Kiyoto Motojima, Kajuro Komeda, Hiroshi Miki, Naoto Kubota, Yasuo Terauchi, Atsuko Tsuchida, Nobuyo Tsuboyama-Kasaoka, Naoko Yamauchi, Tomohiro Ide, Wataru Hori, Shigeaki Kato, Masashi Fukayama, Yasuo Akanuma, Osamu Ezaki, Akiko Itai, Ryozo Nagai, Satoshi Kimura, Kazuyuki Tobe, Hiroyuki Kagechika, Koichi Shudo, Takashi Kadowaki
Toshimasa Yamauchi, Hironori Waki, Junji Kamon, Koji Murakami, Kiyoto Motojima, Kajuro Komeda, Hiroshi Miki, Naoto Kubota, Yasuo Terauchi, Atsuko Tsuchida, Nobuyo Tsuboyama-Kasaoka, Naoko Yamauchi, Tomohiro Ide, Wataru Hori, Shigeaki Kato, Masashi Fukayama, Yasuo Akanuma, Osamu Ezaki, Akiko Itai, Ryozo Nagai, Satoshi Kimura, Kazuyuki Tobe, Hiroyuki Kagechika, Koichi Shudo, Takashi Kadowaki
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Article

Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes

Abstract

PPARγ is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPARγ 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 PPARγ activity observed in heterozygous PPARγ-deficient mice or the Pro12Ala polymorphism in human PPARγ, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPARγ/RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPARγ 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 PPARγ-deficient mice with an RXR antagonist or a PPARγ 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 PPARγ/RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.

Authors

Toshimasa Yamauchi, Hironori Waki, Junji Kamon, Koji Murakami, Kiyoto Motojima, Kajuro Komeda, Hiroshi Miki, Naoto Kubota, Yasuo Terauchi, Atsuko Tsuchida, Nobuyo Tsuboyama-Kasaoka, Naoko Yamauchi, Tomohiro Ide, Wataru Hori, Shigeaki Kato, Masashi Fukayama, Yasuo Akanuma, Osamu Ezaki, Akiko Itai, Ryozo Nagai, Satoshi Kimura, Kazuyuki Tobe, Hiroyuki Kagechika, Koichi Shudo, Takashi Kadowaki

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One possible model for the relationship between PPARγ/RXR activity and i...
One possible model for the relationship between PPARγ/RXR activity and insulin sensitivity on the HF diet. The relationship between PPARγ/RXR activity and WAT mass may be linear. There may appear to be an optimal level of PPARγ/RXR activity for insulin sensitivity that is approximately 0.3–0.5 times normal. Increases in PPARγ/RXR activity as compared with the optimal range are associated with decreased serum leptin levels due to increased PPARγ/RXR-mediated suppression of leptin gene transcription, and decreases in PPARγ/RXR activity may be associated with decreased serum leptin levels due to depletion of WAT. Thus, these data raise the possibility that the relationship between PPARγ/RXR activity and leptin is an inverted U-shaped curve. The relationship between PPARγ/RXR activity and insulin resistance appears to exhibit such a U-shaped curve. Thus, impairment of the leptin pathway may closely parallel impairment of insulin sensitivity.