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This version published online on June 15, 2006
Endocrinology, doi:10.1210/en.2005-1536
A more recent version of this article appeared on September 1, 2006
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Submitted on December 5, 2005
Accepted on June 5, 2006

PPAR{alpha} null mice have increased white adipose tissue glucose utilization, GLUT4, and fat mass. role in liver and brain

Claude Knauf, Jennifer Rieusset, Marc Foretz, Patrice D. Cani, Marc Uldry, Masaya Hosokawa, Estelle Martinez, Matthieu Bringart, Aurélie Waget, Sander Kersten, Béatrice Desvergne, Sandrine Gremlich, Walter Wahli, Josiane Seydoux, Nathalie M. Delzenne, Bernard Thorens, and Rémy Burcelin*

UMR 5018 CNRS-University Paul Sabatier, IFR 31, Bt L1 Rue J. Poulhès, 31403 Toulouse, France.; Institut de Biologie Animale, Université de Lausanne, CH-1015 Lausanne, Switzerland.; Département de Physiologie, Faculté de médecine, Université de Genève, CH-1211 Genève, Switzerland.; Institut de Pharmacologie et de Toxicologie, Université de Lausanne, CH-1005 Lausanne, Switzerland.; Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Université Catholique de Louvain, Brussels, Belgium

* To whom correspondence should be addressed. E-mail: burcelin{at}toulouse.inserm.fr.

Activation of the peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here, we compared PPAR{alpha} KO mice with wild-type and confirmed that the former developed hypoglycemia during fasting. This was associated with only a slight increase in insulin sensitivity but a dramatic increase in whole body and adipose tissue glucose utilization rates in the fasting state. The white subcutaneous and visceral fat depots were larger due to an increase in the size and number of adipocytes and their level of GLUT4 expression was higher and no longer regulated by the fed-to-fast transition. To evaluate whether these adipocyte deregulations were secondary to the absence of PPAR{alpha} from liver, we re-expresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. While more than 90% of the hepatocytes were infected and PPAR{alpha} expression was restored to normal levels, the whole body glucose utilization rate remained elevated. Next, to evaluate whether brain PPAR{alpha} could affect glucose homeostasis, we activated brain PPAR{alpha} in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole body glucose utilization was reduced. Hence our data show that PPAR{alpha} is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation and adipose tissue glucose utilization by a mechanism which does not require PPAR{alpha} expression in the liver. By contrast, activation of PPAR{alpha} in the brain stimulates peripheral glucose utilization. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPAR{alpha} in the brain.
Key words: transcription factor • liver • GLUT4 • autonomic nervous system • glucose transport




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