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J. Biol. Chem., Vol. 279, Issue 49, 50743-50753, December 3, 2004

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Transcript Profiling Suggests That Differential Metabolic Adaptation of Mice to a High Fat Diet Is Associated with Changes in Liver to Muscle Lipid Fluxes^*

Valérie de Fourmestraux, Heike Neubauer, Carine Poussin, Pierre Farmer¶, Laurent Falquet¶, Rémy Burcelin||, Mauro Delorenzi¶, and Bernard Thorens**

From the Institute of Physiology University of Lausanne, Lausanne CH-1005, Switzerland, the ^¶National Center of Competence in Research Molecular Oncology, Institut Suisse de Recherche Expérimentale sur le Cancer and Swiss Institute of Bioinformatics, Epalinges 1066, Switzerland, and the ^||Unité Mixte de Recherche 5018-CNRS-University Paul Sabatier, IFR31 Centre Hospitalier Universitaire, Rangueil, Toulouse 31403, France

Genetically homogenous C57Bl/6 mice display differential metabolic adaptation when fed a high fat diet for 9 months. Most become obese and diabetic, but a significant fraction remains lean and diabetic or lean and non-diabetic. Here, we performed microarray analysis of "metabolic" transcripts expressed in liver and hindlimb muscles to evaluate: (i) whether expressed transcript patterns could indicate changes in metabolic pathways associated with the different phenotypes, (ii) how these changes differed from the early metabolic adaptation to short term high fat feeding, and (iii) whether gene classifiers could be established that were characteristic of each metabolic phenotype. Our data indicate that obesity/diabetes was associated with preserved hepatic lipogenic gene expression and increased plasma levels of very low density lipoprotein and, in muscle, with an increase in lipoprotein lipase gene expression. This suggests increased muscle fatty acid uptake, which may favor insulin resistance. In contrast, the lean mice showed a strong reduction in the expression of hepatic lipogenic genes, in particular of Scd-1, a gene linked to sensitivity to diet-induced obesity; the lean and non-diabetic mice presented an additional increased expression of eNos in liver. After 1 week of high fat feeding the liver gene expression pattern was distinct from that seen at 9 months in any of the three mouse groups, thus indicating progressive establishment of the different phenotypes. Strikingly, development of the obese phenotype involved re-expression of Scd-1 and other lipogenic genes. Finally, gene classifiers could be established that were characteristic of each metabolic phenotype. Together, these data suggest that epigenetic mechanisms influence gene expression patterns and metabolic fates.

Received for publication, July 15, 2004 , and in revised form, September 15, 2004.

^* This work was supported by a grant from the European Union (Genomics Integrated Force for Type 2 Diabetes) and by Grant 3100-065219-01 from the Swiss National Science Foundation (to B. T.). Analyses were performed using BRB ArrayTools developed by Dr. Richard Simon and Amy Peng. 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 text, Figs. S1 and S2, and Tables S1–S5.

These authors contributed equally to this work.

^** To whom correspondence should be addressed. Tel.: 41-21-692-5390; Fax: 41-21-692-5355; E-mail: Bernard.Thorens{at}iphysiol.unil.ch.

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