title: B-1a lymphocytes attenuate insulin resistance.
abstract: Obesity-associated insulin resistance, a common precursor of type 2 diabetes, is characterized by chronic inflammation of tissues, including visceral adipose tissue (VAT). Here we show that B-1a cells, a subpopulation of B lymphocytes, are novel and important regulators of this process. B-1a cells are reduced in frequency in obese high-fat diet (HFD)-fed mice, and EGFP interleukin-10 (IL-10) reporter mice show marked reductions in anti-inflammatory IL-10 production by B cells in vivo during obesity. In VAT, B-1a cells are the dominant producers of B cell-derived IL-10, contributing nearly half of the expressed IL-10 in vivo. Adoptive transfer of B-1a cells into HFD-fed B cell-deficient mice rapidly improves insulin resistance and glucose tolerance through IL-10 and polyclonal IgM-dependent mechanisms, whereas transfer of B-2 cells worsens metabolic disease. Genetic knockdown of B cell-activating factor (BAFF) in HFD-fed mice or treatment with a B-2 cell-depleting, B-1a cell-sparing anti-BAFF antibody attenuates insulin resistance. These findings establish B-1a cells as a new class of immune regulators that maintain metabolic homeostasis and suggest manipulation of these cells as a potential therapy for insulin resistance.
authors.affiliation: Shanghai Institute of Immunology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Melissa Hui Yen
authors.initials: MH
authors.lastname: Chng
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Alonso
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA.
authors.forename: Robert
authors.initials: R
authors.lastname: Yuan
authors.affiliation: Division of Cellular & Molecular Biology, Diabetes Research Group, Toronto General Research Institute (TGRI), University Health Network, Toronto, Ontario, Canada edengleman@stanford.edu dan.winer@uhn.ca.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Winer
authors.affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA edengleman@stanford.edu dan.winer@uhn.ca.
authors.forename: Edgar G
authors.initials: EG
authors.lastname: Engleman
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000502:physiology*; D001786:Blood Glucose; D004041:Dietary Fats / Q000008:administration & dosage / Q000633:toxicity; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D018149:Glucose Intolerance; D006801:Humans; D007075:Immunoglobulin M; D007333:Insulin Resistance / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D007075:Immunoglobulin M; D016753:Interleukin-10