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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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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Both the RXR antagonist HX531 and the PPARγ antagonist BADGE exert antio...
Both the RXR antagonist HX531 and the PPARγ antagonist BADGE exert antiobesity and antidiabetic effects in part through leptin-dependent pathways (a and b). Rectal temperature (a) and oxygen consumption (b) of KKAy mice untreated or treated with HX531 (+HX531) for 2 weeks while on the HF diet or the HC diet. Serum leptin levels of C57 (c) or KKAy mice (d) untreated or treated with HX531, BADGE (+BADGE), or LG100268 (+LG) for 2 weeks while on the HF diet. The left sides of the arrows are before-treatment (c) and after 1-week treatment (d) levels. (e) Leptin protein levels in the medium of 3T3L1 adipocytes treated with 10 μM HX531, 1 μM LG100268, or 100 nM rosiglitazone (Rosi) for 24 hours. (f) Effects of intraperitoneal leptin administration in untreated C57 mice or C57 mice treated with HX531 for 10 days while on the HF diet. Groups of untreated mice or mice treated with HX531 received an intraperitoneal injection of either leptin (10 μg/g/d) (+) or isotonic sodium chloride solution (–). Food intake/12 h (left) and weight changes/12 h (right) were measured. (g and h) WAT weight (g) and insulin resistance index (7) (h) of C57 and db/db mice untreated or treated with HX531 or BADGE for 2 weeks while on the HF diet. The results are expressed as the percentage of the value of untreated mice on the HF diet (g and h). Each bar represents the mean ± SE (n = 5–10). *P < 0.05, **P < 0.01, C57 versus db/db or untreated versus treated with HX531, BADGE, Rosi, LG, or leptin.