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Peroxisome Proliferator-Activated Receptor--Null Mice Have Increased White Adipose Tissue Glucose Utilization, GLUT4, and Fat Mass: Role in Liver and Brain

Unité Mixté de Recherche 5018 (C.K., P.D.C., E.M., M.B., A.W., R.B.), Centre National de la Recherche Scientifique, University Paul Sabatier, 31403 Toulouse, France; Institut de Biologie Animale (J.R., S.K., B.D., S.G., W.W.), Université de Lausanne, CH-1015 Lausanne, Switzerland; Département de Physiologie (J.S.), Faculté de Médecine, Université de Genève, CH-1211 Genève, Switzerland; Institut de Pharmacologie et de Toxicologie (M.F., M.U., M.H., B.T.), Université de Lausanne, CH-1005 Lausanne, Switzerland; and Unit of Pharmacokinetics, Metabolism, Nutrition, and Toxicology (P.D.C., N.M.D.), Université Catholique de Louvain, B-1348 Brussels, Belgium

Address all correspondence and requests for reprints to: Rémy Burcelin, Unit Mixté de Recherche, 5018 Centre National de la Recherche Scientifique-University Paul Sabatier, IFR 31, Bt L1 Rue J. Poulhès, 31403 Toulouse, France. E-mail: burcelin{at}toulouse.inserm.fr.

Activation of the peroxisome proliferator-activated receptor (PPAR)- 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 knockout 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 use rates in the fasting state. The white sc 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 from liver, we reexpresssed this transcription factor in the liver of knockout mice using recombinant adenoviruses. Whereas more than 90% of the hepatocytes were infected and PPAR expression was restored to normal levels, the whole-body glucose use rate remained elevated. Next, to evaluate whether brain PPAR could affect glucose homeostasis, we activated brain PPAR in wild-type mice by infusing WY14643 into the lateral ventricle and showed that whole-body glucose use was reduced. Hence, our data show that PPAR is involved in the regulation of glucose homeostasis, insulin sensitivity, fat accumulation, and adipose tissue glucose use by a mechanism that does not require PPAR expression in the liver. By contrast, activation of PPAR in the brain stimulates peripheral glucose use. This suggests that the alteration in adipocyte glucose metabolism in the knockout mice may result from the absence of PPAR in the brain.

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