title: PAFR in adipose tissue macrophages is associated with anti-inflammatory phenotype and metabolic homoeostasis.
abstract: Metabolic dysfunction is associated with adipose tissue inflammation and macrophage infiltration. PAFR (platelet-activating factor receptor) is expressed in several cell types and binds to PAF (platelet-activating factor) and oxidized phospholipids. Engagement of PAFR in macrophages drives them towards the anti-inflammatory phenotype. In the present study, we investigated whether genetic deficiency of PAFR affects the phenotype of ATMs (adipose tissue macrophages) and its effect on glucose and insulin metabolism. PARFKO (PAFR-knockout) and WT (wild-type) mice were fed on an SD (standard diet) or an HFD (high-fat diet). Glucose and insulin tolerance tests were performed by blood monitoring. ATMs were evaluated by FACS for phenotypic markers. Gene and protein expression was investigated by real-time reverse transcription-quantitative PCR and Western blotting respectively. Results showed that the epididymal adipose tissue of PAFRKO mice had increased gene expression of Ccr7, Nos2, Il6 and Il12, associated with pro-inflammatory mediators, and reduced expression of the anti-inflammatory Il10. Moreover, the adipose tissue of PAFRKO mice presented more pro-inflammatory macrophages, characterized by an increased frequency of F4/80(+)CD11c(+) cells. Blood monocytes of PAFRKO mice also exhibited a pro-inflammatory phenotype (increased frequency of Ly6C(+) cells) and PAFR ligands were detected in the serum of both PAFRKO and WT mice. Regarding metabolic parameters, compared with WT, PAFRKO mice had: (i) higher weight gain and serum glucose concentration levels; (ii) decreased insulin-stimulated glucose disappearance; (iii) insulin resistance in the liver; (iv) increased expression of Ldlr in the liver. In mice fed on an HFD, some of these changes were potentiated, particularly in the liver. Thus it seems that endogenous ligands of PAFR are responsible for maintaining the anti-inflammatory profile of blood monocytes and ATMs under physiological conditions. In the absence of PAFR signalling, monocytes and macrophages acquire a pro-inflammatory phenotype, resulting in adipose tissue inflammation and metabolic dysfunction.
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Luciano Ribeiro
authors.initials: LR
authors.lastname: Filgueiras
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Marianna Mainardi
authors.initials: MM
authors.lastname: Koga
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Paula G
authors.initials: PG
authors.lastname: Quaresma
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Edson Kiyotaka
authors.initials: EK
authors.lastname: Ishizuka
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Marlise B A
authors.initials: MB
authors.lastname: Montes
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, SP, Brazil School of Applied Sciences, State University of Campinas (UNICAMP), Limeira, SP, Brazil.
authors.forename: Patricia O
authors.initials: PO
authors.lastname: Prada
authors.affiliation: Department of Internal Medicine, State University of Campinas (UNICAMP), Campinas, SP, Brazil.
authors.forename: Mario J
authors.initials: MJ
authors.lastname: Saad
authors.affiliation: Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
authors.forename: Sonia
authors.initials: S
authors.lastname: Jancar
authors.affiliation: Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow G12 8TA, U.K. Francisco.Rios@glasgow.ac.uk.
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Rios
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004734:Energy Metabolism; D005786:Gene Expression Regulation; D005838:Genotype; D006706:Homeostasis; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008024:Ligands; D008264:Macrophages / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D010641:Phenotype; D010980:Platelet Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015430:Weight Gain
chemical_list: D001786:Blood Glucose; D018836:Inflammation Mediators; D007328:Insulin; D008024:Ligands; D010980:Platelet Membrane Glycoproteins; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor
keywords: adipose tissue; glucose; insulin; macrophages; platelet-activating factor receptor