UCP1 Induction during Recruitment of Brown Adipocytes in White Adipose Tissue Is Dependent on Cyclooxygenase Activity Lise Madsen1,2*, Lone M. Pedersen3, Haldis Haukaas Lillefosse1,2, Even Fjære1,2, Ingeborg Bronstad 4 , Qin Hao 1 , Rasmus K. Petersen 1 , Philip Hallenborg1, Tao Ma 1 , Rita De Matteis5, Pedro Araujo2, Josep Mercader6, M. Luisa Bonet6, Jacob B. Hansen7, Barbara Cannon8, Jan Nedergaard8, Jun Wang1,9, Saverio Cinti10, Peter Voshol11, Stein Ove Døskeland 4 , Karsten Kristiansen1,9* 1 Department of Biology, University of Copenhagen, Copenhagen, Denmark, 2 National Institute of Nutrition and Seafood Research, Bergen, Norway, 3 Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark, 4 Department of Biomedicine, University of Bergen, Bergen, Norway, 5 Department of Biomolecular Sciences, University of Urbino, Urbino, Italy, 6 Laboratory of Molecular Biology, Nutrition and Biotechnology, Universitat de les Illes Balears, and CIBER de Fisiopatolog´ıa de la Obesidad y Nutricio´ n (CIBERobn), Palma de Mallorca, Spain, 7 Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark, 8 The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden, 9 BGI-Shenzhen, Shenzhen, China, 10 Department of Molecular Pathology and Innovative Therapies, University of Ancona, Ancona, Italy, 11 Metabolic Research Laboratories, University of Cambridge, Cambridge, United Kingdom Abstract Background: The uncoupling protein 1 (UCP1) is a hallmark of brown adipocytes and pivotal for cold- and diet-induced thermogenesis. Methodology/Principal Findings: Here we report that cyclooxygenase (COX) activity and prostaglandin E2 (PGE2) are crucially involved in induction of UCP1 expression in inguinal white adipocytes, but not in classic interscapular brown adipocytes. Cold-induced expression of UCP1 in inguinal white adipocytes was repressed in COX2 knockout (KO) mice and by administration of the COX inhibitor indomethacin in wild-type mice. Indomethacin repressed b-adrenergic induction of UCP1 expression in primary inguinal adipocytes. The use of PGE2 receptor antagonists implicated EP4 as a main PGE2 receptor, and injection of the stable PGE2 analog (EP3/4 agonist) 16,16 dm PGE2 induced UCP1 expression in inguinal white adipose tissue. Inhibition of COX activity attenuated diet-induced UCP1 expression and increased energy efficiency and adipose tissue mass in obesity-resistant mice kept at thermoneutrality. Conclusions/Significance: Our findings provide evidence that induction of UCP1 expression in white adipose tissue, but not in classic interscapular brown adipose tissue is dependent on cyclooxygenase activity. Our results indicate that cyclooxygenase-dependent induction of UCP1 expression in white adipose tissues is important for diet-induced thermogenesis providing support for a surprising role of COX activity in the control of energy balance and obesity development. Citation: Madsen L, Pedersen LM, Lillefosse HH, Fjære E, Bronstad I, et al. (2010) UCP1 Induction during Recruitment of Brown Adipocytes in White Adipose Tissue Is Dependent on Cyclooxygenase Activity. PLoS ONE 5(6): e11391. doi:10.1371/journal.pone.0011391 Editor: Aimin Xu, University of Hong Kong, China Received May 19, 2010; Accepted May 30, 2010; Published June 30, 2010 Copyright: 2010 Madsen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was supported by the Danish Natural Science Research Council, the Novo Nordisk Foundation and the Carlsberg Foundation. Part of the work was carried out as a part of the research program of the Danish Obesity Research Centre (DanORC). DanORC is supported by The Danish Council for Strategic Research (Grant No 2101 06 0005). CIBER de Fisiopatologia de la Obesidad y Nutricio´ n is an initiative of the ISCIII. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: kk@bio.ku.dk (KK); lise.madsen@nifes.no (LM) Introduction The two types of adipose tissues, white (WAT) and brown (BAT), have opposite functions in whole body energy homeostasis. Whereas white adipocytes store excess energy as fat, brown adipocytes contain a large number of mitochondria dedicated to convert fat into heat through uncoupled respiration. The uncoupling of respiration and the resulting heat dissipation depend on the expression of the uncoupling protein 1 (UCP1). UCP1 is an integral membrane protein unique to brown adipocyte mitochondria, where it acts as a proton channel to uncouple oxidative phosphorylation by dissipating the proton gradient across the inner mitochondrial membrane [1]. In mice, an increased content of UCP1 in adipose tissue mitochondria is strongly linked to protection against diet- induced obesity. This is true whether increased UCP1 expression is induced by transgenic expression of UCP1 itself [2;3], of forkhead box 2 (FOXC2) [4], of PR domain containing 16 (PRDM16) [5] or by disruption of the RIIb subunit of protein kinase A [6;7], eukaryotic translation initiation factor E4-binding protein 1 (4E- BP1) [8], cell death inducing DFFA like effector A and C (Cidea and Cidec/Fsp27) [9], the p160 coregulator TIF2 [10] or retinoblasto- ma Rb [11–13]. PLoS ONE | www.plosone.org 1 June 2010 | Volume 5 | Issue 6 | e11391