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Differential Regulation of Peroxisome Proliferator-Activated Receptor (PPAR)-1 and Truncated PPAR2 as an Adaptive Response to Fasting in the Control of Hepatic Peroxisomal Fatty Acid β-Oxidation in the Hibernating Mammal

Institut National de la Santé et de la Recherche Médicale (Z.E.K., P.A., N.L., M.C.-M.), Unité Mixté de Recherche 866, and Centre de Recherche-Biochimie Métabolique et Nutritionnelle, Faculté des Sciences Gabriel, Université de Bourgogne, Groupement de Recherche Centre National de la Recherche Scientifique 2583, Dijon F-21000, France; Laboratoire de Biochimie Biologie Moléculaire (Z.E.K., D.M., M.K., M.S.E.K.), Faculté des Sciences, Université Hassan II, Casablanca, Morocco; Laboratoire de Biologie Cellulaire et Développement (H.S., M.D.), EA 3446, Université Henri Poincaré-Nancy I, Faculté des Sciences, 54506 Vandoeuvre-les-Nancy, France

Address all correspondence and requests for reprints to: M. Cherkaoui-Malki, Centre de Recherche, Institut National de la Santé et de la Recherche Médicale, Unit 866, Centre de Recherche-Biochimie Métabolique et Nutritionnelle, 6, Bd Gabriel, 21000 Dijon, France. E-mail: malki{at}u-bourgogne.fr.

Seasonal obesity and fasting-associated hibernation are the two major metabolic events governing hepatic lipid metabolism in hibernating mammals. In this process, however, the role of the nuclear receptor known as peroxisome proliferator-activated receptor (PPAR)- has not been elucidated yet. Here we show, as in human, that jerboa (Jaculus orientalis) liver expresses both active wild-type PPAR (PPAR1wt) and truncated PPAR forms and that the PPAR1wt to truncated PPAR2 ratio, which indicates the availability of active PPAR1wt, is differentially regulated during fasting-associated hibernation. Functional activation of hepatic jerboa PPAR, during prehibernating and hibernating states, was demonstrated by the induction of its target genes, which encode peroxisomal proteins such as acyl-CoA oxidase 1, peroxisomal membrane protein 70, and catalase, accompanied by a concomitant induction of PPAR thermogenic coactivator PPAR coactivator-1. Interestingly, sustained activation of PPAR by its hypolipidemic ligand, ciprofibrate, abrogates the adaptive fasting response of PPAR during prehibernation and overinduces its target genes, disrupting the prehibernation fattening process. In striking contrast, during fasting-associated hibernation, jerboas exhibit preferential up-regulation of hepatic peroxisomal fatty acid oxidation instead of the mitochondrial pathway, which is down-regulated. Taken together, our results strongly suggest that PPAR is subject to a hibernation-dependent splicing regulation in response to feeding-fasting conditions, which defines the activity of PPAR and the activation of its target genes during hibernation bouts of jerboas.

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				C. J. Nelson, J. P. Otis, and H. V. Carey A role for nuclear receptors in mammalian hibernation J. Physiol., May 1, 2009; 587(9): 1863 - 1870. [Abstract] [Full Text] [PDF]