Submitted on December 11, 2007
Revised on January 30, 2008
Accepted on February 28, 2008
TG-interacting factor is required for the differentiation of preadipocytes
Takahiro Horie, Koh Ono, Minako Kinoshita, Hitoo Nishi, Kazuya Nagao, Teruhisa Kawamura, Yukiko Abe, Hiromichi Wada, Akira Shimatsu, Toru Kita, and Koji Hasegawa
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8507
Corresponding Author: kohono{at}kuhp.kyoto-u.ac.jp
The accumulation of visceral adipose tissue is closely associated with insulin resistance and metabolic syndrome. Therefore, it is important to identify genes that are required for adipocyte differentiation. To identify genes that are required for the differentiation of 3T3-L1 preadipocytes into mature adipocytes, we used retrovirus insertion-mediated random mutagenesis to generate 3T3-L1 cell lines that lose their ability to differentiate into mature adipocytes. One of the genes identified was TG-interacting factor (TGIF), a DNA-binding homeodomain protein that has been demonstrated to suppress Smad-mediated activation of TGF-
-regulated transcription. In TGIF-disrupted clone of 3T3-L1 preadipocytes, the rate of differentiation into mature adipocytes was clearly reduced compared with that in the wild-type clone. Suppression of TGIF by lentivirus-mediated RNAi also inhibited the differentiation of 3T3-L1 cells. Insulin specifically increased the abundance of TGIF protein primarily by enhancing its stability. In addition, insulin caused the rapid accumulation of TGIF in the nuclei. Forced expression of exogenous TGIF repressed both endogenous and overexpressed Smad2/3 -mediated promoter activity in 3T3-L1. These findings suggest that insulin specifically antagonizes TGF- signaling in preadipocytes by stabilizing the putative Smad transcriptional corepressor TGIF and regulates adipocyte differentiation.
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