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Papers In Press, published online ahead of print April 1, 2008
J. Lipid Res., doi:10.1194/jlr.M700545-JLR200

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Journal of Lipid Research, Vol. 49, 880-892, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

TRB3 suppresses adipocyte differentiation by negatively regulating PPAR transcriptional activity

Yu Takahashi^1,*, Nobumichi Ohoka^1,*,, Hidetoshi Hayashi^2, and Ryuichiro Sato^2,*,

^* Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo 113-8657, Japan
Basic Research Activities for Innovative Biosciences, Tokyo 105-0001, Japan
Department of Molecular Health Sciences, Graduate School of Pharmaceutical Sciences, Nagoya City University, Mizuho, Nagoya 467-8603, Japan

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of four figures.

Published, JLR Papers in Press, January 10, 2008.

¹ Y. Takahashi and N. Ohoka contributed equally to this work.

² To whom correspondence should be addressed. e-mail: hhayashi{at}phar.nagoya-cu.ac.jp (H.H.);aroysato{at}mail.ecc.u-tokyo.ac.jp (R.S.)

In the course of an effort to identify the regulators for peroxisome proliferator-activated receptor (PPAR)-dependent perilipin gene expression, we found that tribbles homolog 3 (TRB3), containing a single kinase domain without enzymatic activity, downregulates PPAR transcriptional activities by protein-protein interaction. We examined the role that TRB3 plays in adipocyte differentiation in 3T3-L1 cells. TRB3 gene and protein expression was increased during adipocyte differentiation concomitantly with an increase in the mRNA levels of CCAAT/enhancer binding protein homologous protein. The physical interaction between TRB3 and PPAR was also verified in 3T3-L1 adipocytes. Forced TRB3 expression in 3T3-L1 cells decreased the mRNA levels of PPAR-target genes and intracellular triglyceride levels, whereas knockdown of TRB3 expression by RNA interference increased them. TRB3 also inhibits PPAR-dependent adipocyte differentiation in lentivirus-mediated PPAR-expressing 3T3-L1 cells. These results provide evidence that TRB3 acts as a potent negative regulator of PPAR, a master regulator of adipocyte differentiation, and tightly controls adipogenesis.

Supplementary key words tribbles homolog 3 • perilipin • triglyceride • 3T3-L1 • peroxisome proliferator-activated receptor

Abbreviations: AF, activation function; C/EBP, CCAAT/enhancer binding protein; CHOP, C/EBP homologous protein; ER, endoplasmic reticulum; GFP, green fluorescent protein; PPAR, peroxisome proliferator-activated receptor; PPRE, PPAR-response element; RXR, retinoid X receptor; shRNA, short hairpin RNA; SREBP, sterol-regulatory element binding protein; TRB3, tribbles homolog 3

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