title: CXCR3 controls T-cell accumulation in fat inflammation.
abstract: OBJECTIVE
  Obesity associates with increased numbers of inflammatory cells in adipose tissue (AT), including T cells, but the mechanism of T-cell recruitment remains unknown. This study tested the hypothesis that the chemokine (C-X-C motif) receptor 3 (CXCR3) participates in T-cell accumulation in AT of obese mice and thus in the regulation of local inflammation and systemic metabolism.
  
  
  RESULTS
  Obese wild-type mice exhibited higher mRNA expression of CXCR3 in periepididymal AT-derived stromal vascular cells compared with lean mice. We evaluated the function of CXCR3 in AT inflammation in vivo using CXCR3-deficient and wild-type control mice that consumed a high-fat diet. Periepididymal AT from obese CXCR3-deficient mice contained fewer T cells than obese controls after 8 and 16 weeks on high-fat diet, as assessed by flow cytometry. Obese CXCR3-deficient mice had greater glucose tolerance than obese controls after 8 weeks, but not after 16 weeks. CXCR3-deficient mice fed high-fat diet had reduced mRNA expression of proinflammatory mediators, such as monocyte chemoattractant protein-1 and regulated on activation, normal T cell expressed and secreted, and anti-inflammatory genes, such as Foxp3, IL-10, and arginase-1 in periepididymal AT, compared with obese controls.
  
  
  CONCLUSIONS
  These results demonstrate that CXCR3 contributes to T-cell accumulation in periepididymal AT of obese mice. Our results also suggest that CXCR3 regulates the accumulation of distinct subsets of T cells and that the ratio between these functional subsets across time likely modulates local inflammation and systemic metabolism.
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Viviane Zorzanelli
authors.initials: VZ
authors.lastname: Rocha
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Eduardo J
authors.initials: EJ
authors.lastname: Folco
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Cafer
authors.initials: C
authors.lastname: Ozdemir
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sheikine
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Thomas
authors.initials: T
authors.lastname: Christen
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Galina K
authors.initials: GK
authors.lastname: Sukhova
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Eva H C
authors.initials: EH
authors.lastname: Tang
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Marcio Sommer
authors.initials: MS
authors.lastname: Bittencourt
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Raul D
authors.initials: RD
authors.lastname: Santos
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.).
authors.forename: David E
authors.initials: DE
authors.lastname: Cohen
authors.affiliation: From the Division of Cardiovascular Medicine (V.Z.R., E.J.F., T.C., G.K.S., E.H.C.T., P.L.), Division of Gastroenterology, Department of Medicine (C.O., D.E.C.), and Division of Nuclear Medicine and Molecular Imaging, Department of Radiology (Y.S.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA; Lipid Clinic Cardiopulmonary Division, Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil (V.Z.R., R.D.S.); Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China (E.H.C.T.); Center for Clinical and Epidemiological Research, Division of Internal Medicine, University Hospital, University of São Paulo Medical School, São Paulo, Brazil (M.S.B.); and Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA (A.D.L.). plibby@rics.bwh.harvard.edu.
authors.forename: Peter
authors.initials: P
authors.lastname: Libby
mesh_terms: D000273:Adipose Tissue / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002634:Chemotaxis, Leukocyte; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015434:Panniculitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors
chemical_list: C515188:Cxcr3 protein, mouse; D018836:Inflammation Mediators; D054367:Receptors, CXCR3
keywords: CXCR3, receptors; adipose tissue; inflammation; lymphocytes; macrophages; obesity