Viviane Zorzanelli Rocha1, Eduardo J Folco1, Cafer Ozdemir1, Yuri Sheikine1, Thomas Christen1, Galina K Sukhova1, Eva H C Tang1, Marcio Sommer Bittencourt1, Raul D Santos1, Andrew D Luster1, David E Cohen1, Peter Libby2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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 obesemice and thus in the regulation of local inflammation and systemic metabolism. APPROACH AND 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-deficientmice contained fewer T cells than obese controls after 8 and 16 weeks on high-fat diet, as assessed by flow cytometry. Obese CXCR3-deficientmice 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 obesemice. 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.
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