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

被引:188
作者
Yamauchi, T
Waki, H
Kamon, J
Murakami, K
Motojima, K
Komeda, K
Miki, H
Kubota, N
Terauchi, Y
Tsuchida, A
Tsuboyama-Kasaoka, N
Yamauchi, N
Ide, T
Hori, W
Kato, S
Fukayama, M
Akanuma, Y
Ezaki, O
Itai, A
Nagai, R
Kimura, S
Tobe, K
Kagechika, H
Shudo, K
Kadowaki, T
机构
[1] Univ Tokyo, Grad Sch Med, Dept Internal Med, Bunkyo Ku, Tokyo 1138655, Japan
[2] Meiji Pharmaceut Univ, Dept Biochem, Tokyo, Japan
[3] Tokyo Med Univ, Anim Res Ctr, Div Lab Anim Sci, Tokyo, Japan
[4] Natl Inst Hlth & Nutr, Div Clin Nutr, Tokyo 162, Japan
[5] Univ Tokyo, Dept Pathol, Grad Sch Med, Tokyo, Japan
[6] Univ Tokyo, Inst Mol & Cellular Biosci, Tokyo, Japan
[7] Asahi Life Fdn, Inst Diabet Care & Res, Tokyo, Japan
[8] Inst Med Mol Design, Tokyo, Japan
[9] Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo, Japan
关键词
D O I
10.1172/JCI12864
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
PPAR gamma is a ligand-activated transcription factor and functions as a heterodimer with a retinoid X receptor (RXR). Supraphysiological activation of PPAR gamma 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 PPAR gamma activity observed in heterozygous PPAR gamma -deficient mice or the Pro 12Ala. polymorphism in human PPAR gamma, has been shown to prevent insulin resistance and obesity induced by a high-fat diet. In this study, we investigated whether functional antagonism toward PPAR gamma /RXR could be used to treat obesity and type 2 diabetes. We show herein that an RXR antagonist and a PPAR gamma 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 PPAR gamma -deficient mice with an RXR antagonist or a PPAR gamma 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 PPAR gamma /RXR may be a logical approach to protection against obesity and related diseases such as type 2 diabetes.
引用
收藏
页码:1001 / 1013
页数:13
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