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J Biol Chem, Vol. 274, Issue 33, 23368-23377, August 13, 1999

Rat Peroxisome Proliferator-activated Receptors and Brown Adipose Tissue Function during Cold Acclimatization

Hebe M. Guardiola-Diaz, Stefan Rehnmark^¶, Nobuteru Usuda^**, Tatjana Albrektsen, Dorothee Feltkamp, Jan-Åke Gustafsson^§§, and Stefan E. H. Alexson^¶¶

From the  Center for Biotechnology, the ^§§ Department of Medical Nutrition, and the ^¶¶ Division of Clinical Chemistry, Huddinge University Hospital, Karolinska Institute, S-141 86, Huddinge, Sweden, the ^¶ Department of Metabolic Research, Wenner-Gren Institute, University of Stockholm, S-106 91, Stockholm, Sweden, and the ^** Department of Anatomy and Cell Biology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390, Japan

Brown adipose tissue (BAT) hyperplasia is a fundamental physiological response to cold; it involves an acute phase of mitotic cell growth followed by a prolonged differentiation phase. Peroxisome proliferator-activated receptors (PPARs) are key regulators of fatty acid metabolism and adipocyte differentiation and may therefore mediate important metabolic changes during non-shivering thermogenesis. In the present study we have investigated PPAR mRNA expression in relation to peroxisome proliferation in rat BAT during cold acclimatization. By immunoelectron microscopy we show that the number of peroxisomes per cytoplasmic volume and acyl-CoA oxidase immunolabeling density remained constant (thus increasing in parallel with tissue mass and cell number) during the initial proliferative phase and the acute thermogenic response but increased after 14 days of cold exposure, correlating with terminal differentiation of BAT. A pronounced decrease in BAT PPAR and PPAR mRNA levels was found within hours of exposure to cold, which was reversed after 14 days, suggesting a role for either or both of these subtypes in the proliferation and induction of peroxisomes and peroxisomal -oxidation enzymes. In contrast, PPAR mRNA levels increased progressively during cold exposure. Transactivation assays in HIB 1B and HEK-293 cells demonstrated an adrenergic stimulation of peroxisome proliferator response element reporter activity via PPAR, establishing a role for these nuclear receptors in hormonal regulation of gene transcription in BAT.

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