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J. Biol. Chem., Vol. 282, Issue 41, 29946-29957, October 12, 2007

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Adipose Tissue Integrity as a Prerequisite for Systemic Energy Balance

A CRITICAL ROLE FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ^*

Silvia I. Anghel, Elodie Bedu, Celine Delucinge Vivier, Patrick Descombes, Béatrice Desvergne, and Walter Wahli¹

From the Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Génopode Bldg., CH-1015 Lausanne, Switzerland and the Genomics Platform, National Research Center Frontiers in Genetics, Geneva University Medical School, CH-1211 Geneva, Switzerland

Peroxisome proliferator-activated receptor (PPAR) is an essential regulator of adipocyte differentiation, maintenance, and survival. Deregulations of its functions are associated with metabolic diseases. We show here that deletion of one PPAR allele not only affected lipid storage but, more surprisingly, also the expression of genes involved in glucose uptake and utilization, the pentose phosphate pathway, fatty acid synthesis, lipolysis, and glycerol export as well as in IR/IGF-1 signaling. These deregulations led to reduced circulating adiponectin levels and an energy crisis in the WAT, reflected in a decrease to nearly half of its intracellular ATP content. In addition, there was a decrease in the metabolic rate and physical activity of the PPAR^+/- mice, which was abolished by thiazolidinedione treatment, thereby linking regulation of the metabolic rate and physical activity to PPAR. It is likely that the PPAR^+/- phenotype was due to the observed WAT dysfunction, since the gene expression profiles associated with metabolic pathways were not affected either in the liver or the skeletal muscle. These findings highlight novel roles of PPAR in the adipose tissue and underscore the multifaceted action of this receptor in the functional fine tuning of a tissue that is crucial for maintaining the organism in good health.

Received for publication, March 22, 2007 , and in revised form, July 16, 2007.

^* This work was supported by Swiss National Science Foundation Grants 31000-11340411 and 3100A0-108295 (to W. W. and B. D., respectively). and by the Etat de Vaud. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S3.

¹ To whom correspondence should be addressed. Tel.: 41-21-692-4110; Fax: 41-21-692-4115; E-mail: walter.wahli{at}unil.ch.

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