Monomeric Tartrate Resistant Acid Phosphatase Induces Insulin Sensitive Obesity Pernilla La˚ ng1, Vanessa van Harmelen2, Mikael Ryde´ n2, Maria Kaaman2, Paolo Parini3, Claes Carneheim4, A. Ian Cassady5, David A. Hume5,6, Go¨ ran Andersson1*, Peter Arner2* 1 Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden, 2 Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden, 3 Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden, 4 Integrative Pharmacology, Biovitrum AB, Stockholm, Sweden, 5 Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia, 6 The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Roslin, United Kingdom Abstract Background: Obesity is associated with macrophage infiltration of adipose tissue, which may link adipose inflammation to insulin resistance. However, the impact of inflammatory cells in the pathophysiology of obesity remains unclear. Tartrate resistant acid phosphatase (TRAP) is an enzyme expressed by subsets of macrophages and osteoclasts that exists either as an enzymatically inactive monomer or as an active, proteolytically processed dimer. Principal Findings: Using mice over expressing TRAP, we show that over-expression of monomeric, but not the dimeric form in adipose tissue leads to early onset spontaneous hyperplastic obesity i.e. many small fat cells. In vitro, recombinant monomeric, but not proteolytically processed TRAP induced proliferation and differentiation of mouse and human adipocyte precursor cells. In humans, monomeric TRAP was highly expressed in the adipose tissue of obese individuals. In both the mouse model and in the obese humans the source of TRAP in adipose tissue was macrophages. In addition, the obese TRAP over expressing mice exhibited signs of a low-grade inflammatory reaction in adipose tissue without evidence of abnormal adipocyte lipolysis, lipogenesis or insulin sensitivity. Conclusion: Monomeric TRAP, most likely secreted from adipose tissue macrophages, induces hyperplastic obesity with normal adipocyte lipid metabolism and insulin sensitivity. Citation: La˚ng P, van Harmelen V, Ryde´n M, Kaaman M, Parini P, et al (2008) Monomeric Tartrate Resistant Acid Phosphatase Induces Insulin Sensitive Obesity. PLoS ONE 3(3): e1713. doi:10.1371/journal.pone.0001713 Editor: Alessandro Bartolomucci, University of Parma, Italy Received July 30, 2007; Accepted February 4, 2008; Published March 5, 2008 Copyright: 2008 La˚ng 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 study was supported by grants from Swedish Research Council, Swedish Heart and Lung Foundation, Novo Nordic Foundation, Swedish Diabetes Association and King Gustaf V, Queen Victoria Foundation and the European Union (HEPADIP, LSHM,-CT-2005-018734). Competing Interests: The authors have declared that no competing interests exist. * E-mail: goran.andersson@ki.se (GA); peter.arner@ki.se (PA) Introduction Adipocytes develop through a chain of events starting with the proliferation of mesenchymal stem cells (MSC) which subsequently differentiate into pre-adipocytes and finally into mature adipocytes [1]. The exact mechanisms regulating these transitions are not completely understood. Among transcription factors, peroxisome proliferator-activated receptor gamma (PPARc) promotes adipo- cyte differentiation [2], while GATA-2, GATA-3 and Wnt inhibit [3,4] this process. Human adipose tissue-derived MSCs can develop into multiple lineages including adipocytes, osteoblasts, chondrocytes and myocytes [5]. Conversely, osteoblasts and adipocytes are able to trans-differentiate [6–8], underscoring the close relationship between these cell types. One possible regulator of osteoblast differentiation and bone formation is the osteoclast-/ macrophage-derived metalloenzyme tartrate-resistant acid phos- phatase (TRAP) [9,10]. TRAP, also known as purple acid phosphatase, uteroferrin or type 5 acid phosphatase (Acp5), exists either as a latent monomeric pro-enzyme of approximately 35 kDa or as a proteolytically processed two-subunit enzyme of approximately 22 and 16 kDa linked by a disulphide bridge [11,12]. The proteolytic processing (exerted by, for instance, cathepsin K) excises part of an exposed loop region close to the active site and is permissive for the catalytic activation of TRAP [13]. TRAP has been shown to exist intracellularly in various cell types and to be secreted in vivo by osteoclasts [14,15] and in vitro by macrophages and osteoclasts [16]. Intracellularly, TRAP is thought to participate in degrada- tion of collagen fragments in osteoclasts [17,18] and of phagocytosed bacteria in macrophages [19]. Osteoclast secreted extracellular TRAP, on the other hand, has been proposed to participate in the regulation of osteoclast adhesion and migration [20]. However, the role of extracellular TRAP secreted from other cell types, including macrophages, is unknown. Macrophages are known to infiltrate adipose tissue during development of obesity [21,22] and have been attributed a function in the link behind obesity and insulin resistance [22,23]. In adipose tissue, macrophages have been proposed to secrete factors that increases expression of inflammatory genes in adipocytes [23,24] and inhibit adipogenesis [24,25]. Furthermore, disruption of PPARc expression in macrophages predisposes mice to development of obesity and insulin resistance [26]. PLoS ONE | www.plosone.org 1 March 2008 | Volume 3 | Issue 3 | e1713