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PPAR Research
Volume 2009 (2009), Article ID 867678, 13 pages
http://dx.doi.org/10.1155/2009/867678
Research Article

Molecular Characterization of the Tumor Suppressor Candidate 5 Gene: Regulation by PPAR and Identification of TUSC5 Coding Variants in Lean and Obese Humans

1Obesity & Metabolism Research Unit, USDA-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA 95616, USA
2Department of Biological Sciences, Department of Biophysics and Chemical Biology, Seoul National University, Seoul 151-742, South Korea
3Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada K1H 8L1
4Graduate Schools of Pharmaceutical Sciences, Osaka University, Osaka 565-0871, Japan
5Department of Pathology, The Feinberg School of Medicine, Northwestern University, Chicago, IL 60208, USA
6Division of Advanced Therapeutics for Metabolic Diseases, Tohoku University Graduate School of Medicine, Sendai 980-8576, Japan
7Pennington Biomedical Research Center, Baton Rouge, LA 70808, USA
8Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
9Institute National de la Santé et de la Recherche Médicale (INSERM) UMR 626, 13385 Marseille and Faculté de Médecine, Université de la Méditerranée, Marseille, France
10Department of Nutrition, University of California, Davis 95616, USA

Received 28 August 2009; Accepted 13 November 2009

Academic Editor: Dipak Panigrahy

Copyright © 2009 Trina A. Knotts et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Tumor suppressor candidate 5 (TUSC5) is a gene expressed abundantly in white adipose tissue (WAT), brown adipose tissue (BAT), and peripheral afferent neurons. Strong adipocyte expression and increased expression following peroxisome proliferator activated receptor (PPAR ) agonist treatment of 3T3-L1 adipocytes suggested a role for Tusc5 in fat cell proliferation and/or metabolism. However, the regulation of Tusc5 in WAT and its potential association with obesity phenotypes remain unclear. We tested the hypothesis that the TUSC5 gene is a bona fide PPAR target and evaluated whether its WAT expression or single-nucleotide polymorphisms (SNPs) in the TUSC5 coding region are associated with human obesity. Induction of Tusc5 mRNA levels in 3T3-L1 adipocytes by troglitazone and GW1929 followed a dose-response consistent with these agents' binding affinities for PPAR . Chromatin immunoprecipitation (ChIP) experiments confirmed that PPAR protein binds a  kb promotor sequence of murine TUSC5 transiently during 3T3-L1 adipogenesis, concurrent with histone H3 acetylation. No change in Tusc5 mRNA or protein levels was evident in type 2 diabetic patients treated with pioglitazone. Tusc5 expression was not induced appreciably in liver preparations overexpressing PPARs, suggesting that tissue-specific factors regulate PPAR responsiveness of the TUSC5 gene. Finally, we observed no differences in Tusc5 WAT expression or prevalence of coding region SNPs in lean versus obese human subjects. These studies firmly establish the murine TUSC5 gene locus as a PPAR target, but the significance of Tusc5 in obesity phenotypes or in the pharmacologic actions of PPAR agonists in humans remains equivocal.