title: Differential chemoattractant response in adipocytes and macrophages to the action of acylation stimulating protein.
abstract: Obesity is characterized by chronic low-grade inflammation with increased adipose tissue pro-inflammatory cytokine production. Acylation stimulating protein (ASP) stimulates triglyceride synthesis and glucose transport via its receptor C5L2. Circulating ASP is increased in obesity, insulin resistance and metabolic syndrome. The present study examines the effects of normal (50 nM), high physiological (200 nM) and pathological (600 nM) levels of ASP on inflammatory changes in 3T3-L1 adipocytes and J774 macrophages and the underlying mechanisms involved. Treatment with ASP for 24h increased monocyte chemoattractant protein-1 (MCP1, 800%, P<0.001) and keratinocyte-derived chemokine (KC, >150%, P<0.01) secretion in adipocytes in a dose-dependent manner, with no effect on IL-6 or adiponectin. In macrophages, ASP had no effect on these cytokines. C5a, a ligand for C5L2 and C5aR receptors, differed from ASP. Macrophage-adipocyte coculture increased MCP-1 and adiponectin secretion, and ASP further enhanced secretion (P<0.001 and P<0.05, respectively) at doses of 50 nM and 200 nM. ASP increased Ser(468) and Ser(536) phosphorylation of p65 NFκB in a time- and concentration-dependent manner (P<0.05) as well as phosphorylation of Akt Ser(473) (p=0.02). ASP and insulin stimulations of Ser(536) p65 NFκB phosphorylation were comparable (both p<0.05) but not additive. Both inhibition of PI3kinase (with wortmannin) and NFκB (with BAY11-7085) prevented ASP stimulation of MCP-1 and KC secretion in adipocytes. These findings suggest that ASP, especially at high physiologic doses, may stimulate specific inflammatory cytokines in adipocytes through PI3kinase- and NFκB-dependant pathways, thus further promoting macrophage infiltration and local inflammation in obese adipose tissue.
authors.affiliation: Centre de Recherche Institut Universitaire de Cardiologie & Pneumologie de Québec, Université Laval, Québec, Canada.
authors.forename: Fun-Qun
authors.initials: FQ
authors.lastname: Tom
authors.forename: Danny
authors.initials: D
authors.lastname: Gauvreau
authors.forename: Marc
authors.initials: M
authors.lastname: Lapointe
authors.forename: HuiLing
authors.initials: H
authors.lastname: Lu
authors.forename: Pegah
authors.initials: P
authors.lastname: Poursharifi
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Luo
authors.forename: Katherine
authors.initials: K
authors.lastname: Cianflone
mesh_terms: D041721:3T3-L1 Cells; D000215:Acylation; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism; D018920:Coculture Techniques; D003176:Complement C3; D017077:Culture Media, Conditioned / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007328:Insulin / Q000494:pharmacology; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology*; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D044087:Receptor, Anaphylatoxin C5a / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; C545610:C3 protein, mouse; C000594938:C5ar2 protein, mouse; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D003176:Complement C3; D017077:Culture Media, Conditioned; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D044087:Receptor, Anaphylatoxin C5a; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D051996:Transcription Factor RelA; C577686:interleukin-6, mouse; C074302:keratinocyte-derived chemokines; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases