title: Protective Role for B-1b B Cells and IgM in Obesity-Associated Inflammation, Glucose Intolerance, and Insulin Resistance.
abstract: OBJECTIVE
  Little is known about the role(s) B cells play in obesity-induced metabolic dysfunction. This study used a mouse with B-cell-specific deletion of Id3 (Id3(Bcell KO)) to identify B-cell functions involved in the metabolic consequences of obesity.
  
  
  RESULTS
  Diet-induced obese Id3(Bcell KO) mice demonstrated attenuated inflammation and insulin resistance in visceral adipose tissue (VAT), and improved systemic glucose tolerance. VAT in Id3(Bcell KO) mice had increased B-1b B cells and elevated IgM natural antibodies to oxidation-specific epitopes. B-1b B cells reduced cytokine production in VAT M1 macrophages, and adoptively transferred B-1b B cells trafficked to VAT and produced natural antibodies for the duration of 13-week studies. B-1b B cells null for Id3 demonstrated increased proliferation, established larger populations in Rag1(-/-) VAT, and attenuated diet-induced glucose intolerance and VAT insulin resistance in Rag1(-/-) hosts. However, transfer of B-1b B cells unable to secrete IgM had no effect on glucose tolerance. In an obese human population, results provided the first evidence that B-1 cells are enriched in human VAT and IgM antibodies to oxidation-specific epitopes inversely correlated with inflammation and insulin resistance.
  
  
  CONCLUSIONS
  NAb-producing B-1b B cells are increased in Id3(Bcell KO) mice and attenuate adipose tissue inflammation and glucose intolerance in diet-induced obese mice. Additional findings are the first to identify VAT as a reservoir for human B-1 cells and to link anti-inflammatory IgM antibodies with reduced inflammation and improved metabolic phenotype in obese humans.
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Daniel B
authors: DB
authors: Harmon
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Prasad
authors: P
authors: Srikakulapu
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Jennifer L
authors: JL
authors: Kaplan
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Stephanie N
authors: SN
authors: Oldham
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Chantel
authors: C
authors: McSkimming
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: James C
authors: JC
authors: Garmey
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Heather M
authors: HM
authors: Perry
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Jennifer L
authors: JL
authors: Kirby
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Thomas A
authors: TA
authors: Prohaska
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Ayelet
authors: A
authors: Gonen
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Peter
authors: P
authors: Hallowell
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Bruce
authors: B
authors: Schirmer
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Sotirios
authors: S
authors: Tsimikas
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Angela M
authors: AM
authors: Taylor
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.).
authors: Joseph L
authors: JL
authors: Witztum
authors: From the Cardiovascular Research Center (D.B.H., P.S., J.L.K., S.N.O., C.M.S., J.C.G., H.M.P., C.A.M.), Department of Biochemistry, Molecular Biology, and Genetics (D.B.H.), Division of Cardiovascular Medicine, Department of Medicine (P.S., A.M.T., C.A.M.), Department of Pathology (J.L.K., H.M.P.), Division of Endocrinology and Metabolism, Department of Medicine (J.L.K.), Department of Surgery (P.H., B.S.), Beirne B. Carter Center for Immunology Research (C.A.M.), Department of Molecular Physiology and Biological Physics (C.A.M.), University of Virginia, Charlottesville; and Department of Medicine, University of California San Diego, La Jolla (T.A.P., A.G., S.T., J.L.W.). cam8c@virginia.edu.
authors: Coleen A
authors: CA
authors: McNamara
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism* / Q000637:transplantation; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D005838:Genotype; D018149:Glucose Intolerance / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007148:Immunoglobulin mu-Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000276:immunology / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D013997:Time Factors; D046509:Tissue Culture Techniques
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D016207:Cytokines; D018398:Homeodomain Proteins; D007148:Immunoglobulin mu-Chains; D018836:Inflammation Mediators; D051796:Inhibitor of Differentiation Proteins; D007328:Insulin; C064658:RAG-1 protein; C067679:Idb3 protein, mouse
keywords: B cells; adipose tissue; cytokines; inflammation; obesity