TY - JOUR
T1 - Inhibition of RXR and PPARγ ameliorates diet-induced obesity and type 2 diabetes
AU - Yamauchi, Toshimasa
AU - Waki, Hironori
AU - Kamon, Junji
AU - Murakami, Koji
AU - Motojima, Kiyoto
AU - Komeda, Kajuro
AU - Miki, Hiroshi
AU - Kubota, Naoto
AU - Terauchi, Yasuo
AU - Tsuchida, Atsuko
AU - Tsuboyama-Kasaoka, Nobuyo
AU - Yamauchi, Naoko
AU - Ide, Tomohiro
AU - Hori, Wataru
AU - Kato, Shigeaki
AU - Fukayama, Masashi
AU - Akanuma, Yasuo
AU - Ezaki, Osamu
AU - Itai, Akiko
AU - Nagai, Ryozo
AU - Kimura, Satoshi
AU - Tobe, Kazuyuki
AU - Kagechika, Hiroyuki
AU - Shudo, Koichi
AU - Kadowaki, Takashi
PY - 2001
Y1 - 2001
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85047685428&partnerID=8YFLogxK
U2 - 10.1172/JCI12864
DO - 10.1172/JCI12864
M3 - 学術論文
C2 - 11581301
AN - SCOPUS:85047685428
SN - 0021-9738
VL - 108
SP - 1001
EP - 1013
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 7
ER -