Molecular Immunology 51 (2012) 73–81 Contents lists available at SciVerse ScienceDirect Molecular Immunology journal homepage: www.elsevier.com/locate/molimm A new effector of lipid metabolism: Complement factor properdin Danny Gauvreau a,b , Christian Roy a,b , Fun-Qun Tom a,b , HuiLing Lu a,b , Pierre Miegueu a,b , Denis Richard a,b , Wen-Chao Song c , Cordula Stover d , Katherine Cianflone a,b,∗ a Institut Universitaire de Cardiologie et de Pneumologie de Quebec Research Center (CRIUCPQ), Quebec, QC, Canada b Department of Medicine, Laval University, Quebec, QC, Canada c Institute for Translational Medicine and Therapeutics, Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA d Department of Infection, Immunity and Inflammation, University of Leicester, Leicester, UK article info Article history: Received 4 November 2011 Received in revised form 1 February 2012 Accepted 6 February 2012 Available online 3 March 2012 Keywords: Properdin Alternative complement pathway Acylation stimulating protein Triglyceride abstract Background: The complement system is well known for its role in innate immunity via the classical, the alternative and the lectin pathways, although recent investigations suggest expanding roles in adipose tissue. Properdin stabilizes C3 convertase following alternative complement activation. Properdin is also present in adipose tissue, localized to adipocyte membranes. Aim: We evaluated the potential role of properdin in energy metabolism using properdin deficient (PKO) mice and cell based assays. Results: PKO mice have a diet-dependent increase in weight gain compared to wild-type (WT) littermates on a high fat diet (P < 0.05), directly related to 51% increase in relative fat mass (PKO: 35.8 ± 2.2% body fat vs. WT: 23.6 ± 2.2%, P < 0.01). PKO mice have decreased energy expenditure (P < 0.01), and altered postprandial lipid clearance (P < 0.01). However glucose metabolism was unchanged after a glucose tol- erance test vs. WT mice. In murine 3T3-L1 adipocytes, addition of properdin had no effect on C3 or ASP production but almost completely inhibited the insulin-mediated stimulation of fatty acid uptake and incorporation into TG. Properdin had no effect on basal or insulin-stimulated glucose transport in either 3T3-L1 adipocytes or L6 rat skeletal muscle cells. Conclusion: Thus properdin may be added to the growing list of complement proteins (C3, adipsin, factor B, ASP (C3adesArg), factor H, C1q and C3aR) which influence lipid metabolism, energy storage and insulin resistance, and further support the hypothesis of a dual role of complement in adipose tissue. © 2012 Elsevier Ltd. All rights reserved. 1. Introduction The complement system is a complex enzymatic cascade consisting of more than 30 plasma proteins. Activation of com- plement can occur through three major pathways: classical, lectin and alternative pathways. Alternative pathway (AP) activation is antibody-independent and is activated through binding to various substances, including viruses, bacteria, fungi but also C-reactive protein, protein A, polysaccharides, tumor cells and damaged cells. Moreover, spontaneous hydrolysis of the complement C3 can also lead to this activation (Ehrnthaller et al., 2011). Recent investigations suggest that activation of the complement system Abbreviations: C3adesArg/ASP, acylation stimulating protein; TG, triglyceride; NEFA, non-esterified fatty acid; PKO, properdin knock-out; RQ, respiratory quotient; DEXA, dual-energy X-ray absorptiometry; CD36/FAT, fatty acid translocase; TSP-1, thrombospondin-1; FIAD, fatty acid incorporation into adipose tissue. ∗ Corresponding author at: Centre de Recherche IUCPQ, Université Laval, Y4332, 2725 Chemin Ste-Foy, Québec, QC, G1V 4G5, Canada. Tel.: +1 418 656 8711x3731; fax: +1 418 656 4749. E-mail address: katherine.cianflone@criucpq.ulaval.ca (K. Cianflone). can occur via additional pathways involving coagulation factors, direct cellular interaction (Huber-Lang et al., 2002) or on specific targets by properdin (Kemper et al., 2010; Kimura et al., 2008). Proximal activation leads to production of C3a and C3adesArg (Acylation Stimulating Protein) and subsequently C5a, while distal activation induces the assembly of the membrane attack complex which leads to formations of pores in target membranes resulting in the death of cells by lysis (Walport, 2001). Physiological functions of complement include defense against infection, interfacing between innate and adaptive immune sys- tems, and the disposal of cellular debris (Walport, 2001). Moreover, complement is also involved in reproductive success, embryonic implantation and tissue regeneration, and the presence of the strong estrogen-response elements in C3 may underlie functions that seem far removed from infectious or inflammatory responses (Pattrick et al., 2009). Properdin is a protein of 53 kDa composed of identical subunits that associate head-to-tail to form dimers, trimers and tetramers (Smith et al., 1984). Each subunit is composed of six globular domains, which are homologous to thrombospondin-1 (TSP-1) (Nolan et al., 1991). Properdin binds to C3b and is involved in alter- 0161-5890/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.molimm.2012.02.110