Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes
Toshimasa Yamauchi, … , Koichi Shudo, Takashi Kadowaki
Toshimasa Yamauchi, … , Koichi Shudo, Takashi Kadowaki
Published October 1, 2001
Citation Information: J Clin Invest. 2001;108(7):1001-1013. https://doi.org/10.1172/JCI12864.
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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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Figure 1

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The RXR antagonist HX531 serves as a functional PPARγ/RXR inhibitor (a a...
The RXR antagonist HX531 serves as a functional PPARγ/RXR inhibitor (a and c). Transactivation analysis of PPARγ/RXR (a), PPARα/RXR (c). CV-1 cells were cotransfected with RXRα with an expression vector for PPARγ or PPARα. PPARγ/RXR or PPARα/RXR activity was assessed on a PPRE-tk LUC (24) as described previously (22, 23). CV-1 cells were treated with the indicated concentrations of rosiglitazone (Rosi), LG100268 (LG), 15-deoxy-Δ12,14 prostaglandin J2 (15d-PGJ2), Wy-14,643 (Wy), BADGE, and HX531. 9-cis-retinoic acid (b) 3T3L1 adipocyte differentiation assay. Oil red O staining for fat accumulation in cells at day 6 after induction. Cells were grown to confluence and then induced to differentiate by exposure to 100 nM rosiglitazone, 1 μM LG100268, or 10 μM HX531, or by conventional hormonal stimuli (MDI; a combination of 3-isobutyl-1-methylxanthine, dexamethasone, and insulin). (d) Amounts of the mRNAs of liver-type fatty acid–binding protein (L-FABP), HD, and long-chain acyl-CoA dehydrogenase (LCAD) in rat hepatoma FAO cells treated with the indicated concentrations of Wy-14,643 and HX531 for 24 hours. Each bar represents the mean ± SE (n = 5–10). *P < 0.05, **P < 0.01 with versus without HX531 or BADGE. NS, no significant difference.