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Altered Growth in Male Peroxisome Proliferator-Activated Receptor (PPAR) Heterozygous Mice: Involvement of PPAR in a Negative Feedback Regulation of Growth Hormone Action

Center for Integrative Genomics (J.R., S.I.A., P.E., L.M., N.S.T., W.W., B.D.), NCCR Frontiers in Genetics, University of Lausanne, CH-1015 Lausanne, Switzerland; Centre Médical Universitaire (J.S.), Département de Physiologie, CH-1211 Geneva 4, Switzerland; and Institut de Génétique et de Biologie Moléculaire et Cellulaire (D.M., P.C.)/Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Médicale/Université Louis Pasteur/Collège de France, 67404 Illkirch cedex, CU de Strasbourg, France

Address all correspondence and requests for reprints to: Professor Béatrice Desvergne, Center for Integrative Genomics, University of Lausanne, Bâtiment de Biologie, CH-1015 Lausanne, Switzerland. E-mail: beatrice.desvergne{at}cig.unil.ch.

The peroxisome proliferator-activated receptor (PPAR) plays a major role in fat tissue development and physiology. Mutations in the gene encoding this receptor have been associated to disorders in lipid metabolism. A thorough investigation of mice in which one PPAR allele has been mutated reveals that male PPAR heterozygous (PPAR +/–) mice exhibit a reduced body size associated with decreased body weight, reflecting lean mass reduction. This phenotype is reproduced when treating the mice with a PPAR- specific antagonist. Monosodium glutamate treatment, which induces weight gain and alters body growth in wild-type mice, further aggravates the growth defect of PPAR +/– mice. The levels of circulating GH and that of its downstream effector, IGF-I, are not altered in mutant mice. However, the IGF-I mRNA level is decreased in white adipose tissue (WAT) of PPAR +/– mice and is not changed by acute administration of recombinant human GH, suggesting an altered GH action in the mutant animals. Importantly, expression of the gene encoding the suppressor of cytokine signaling-2, which is an essential negative regulator of GH signaling, is strongly increased in the WAT of PPAR +/– mice. Although the relationship between the altered GH signaling in WAT and reduced body size remains unclear, our results suggest a novel role of PPAR in GH signaling, which might contribute to the metabolic disorder affecting insulin signaling in PPAR mutant mice.

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Nuclear Receptors:   PPARγ

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