title: C5aR and C5L2 act in concert to balance immunometabolism in adipose tissue.
abstract: Recent studies suggested that the immunometabolic receptors; C5aR and C5L2, constitutively self-associate into homo-/heterodimers and that acylation stimulating protein (ASP/C3adesArg) or C5a treatment of adipocytes increased their colocalization. The present study evaluates the C5aR contribution in adipocytes to the metabolic and immune responses elicited by ligand stimulation. The effects of C5a, ASP, and insulin on cytokine production, triglyceride synthesis (TGS), and key signaling pathways were evaluated in isolated primary adipocytes and cultured 3T3-L1 differentiated adipocytes. In addition, mRNA expression of IRS1 and PGC1α was compared in adipose tissue samples from WT vs. C5aRKO mice. Both C5a and ASP directly increased MCP-1 (238±4%; P<0.001, and 377±2% vs. basal 100%; P<0.001, respectively) and KC (413±11%; P<0.001, and 529±16%; P<0.001 vs. basal 100%, respectively) secretion, TGS (131±1%; P<0.001, and 152±6%; P<0.001, vs. basal 100% respectively), and Akt/NFκB phosphorylation pathways in adipocytes. However, in C5aRKO adipocytes, C5a effects were disrupted, while stimulatory effects of ASP were mostly maintained. Addition of C5a completely blocked ASP signaling and activity in both C5aRKO and WT adipocytes as well as 3T3-L1 adipocytes. Furthermore, C5aRKO adipocytes revealed impaired insulin stimulation of cytokine production, with partial impairment of signaling and TGS stimulation, consistent with decreased IRS1 and PGC1α mRNA expression in adipose tissue. These observations indicate the importance of C5aR in adipose tissue metabolism and immunity, which may be regulated through heterodimerization with C5L2.
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC, Canada; Department of Medicine, Laval University, Québec, QC, Canada.
authors.forename: Pegah
authors.initials: P
authors.lastname: Poursharifi
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC, Canada.
authors.forename: Marc
authors.initials: M
authors.lastname: Lapointe
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC, Canada; Department of Medicine, Laval University, Québec, QC, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Fisette
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC, Canada.
authors.forename: Huiling
authors.initials: H
authors.lastname: Lu
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC, Canada; Department of Medicine, Laval University, Québec, QC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Roy
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC, Canada; Department of Medicine, Laval University, Québec, QC, Canada.
authors.forename: Mercedes Nancy
authors.initials: MN
authors.lastname: Munkonda
authors.affiliation: Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland 4072, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Québec, QC, Canada; Department of Medicine, Laval University, Québec, QC, Canada. Electronic address: katherine.cianflone@criucpq.ulaval.ca.
authors.forename: Katherine
authors.initials: K
authors.lastname: Cianflone
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000276:immunology; D000273:Adipose Tissue / Q000276:immunology* / Q000378:metabolism*; D000818:Animals; D003176:Complement C3; D015936:Complement C5a / Q000378:metabolism; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008954:Models, Biological; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology
chemical_list: C545610:C3 protein, mouse; C000594938:C5ar2 protein, mouse; D003176:Complement C3; D036341:Intercellular Signaling Peptides and Proteins; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D015936:Complement C5a
keywords: ASP; Acylation Stimulating Protein/C3adesArg; Adipose tissue; C5L2; C5aR-like receptor 2; Complement C5a; G protein-coupled receptor; GPCR; Inflammation; KC; MCP-1; Serpentine receptor; TGS; acylation stimulating protein; keratinocyte chemoattractant; monocyte chemoattractant protein -1; triglyceride synthesis