title: B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies.
abstract: Chronic inflammation characterized by T cell and macrophage infiltration of visceral adipose tissue (VAT) is a hallmark of obesity-associated insulin resistance and glucose intolerance. Here we show a fundamental pathogenic role for B cells in the development of these metabolic abnormalities. B cells accumulate in VAT in diet-induced obese (DIO) mice, and DIO mice lacking B cells are protected from disease despite weight gain. B cell effects on glucose metabolism are mechanistically linked to the activation of proinflammatory macrophages and T cells and to the production of pathogenic IgG antibodies. Treatment with a B cell-depleting CD20 antibody attenuates disease, whereas transfer of IgG from DIO mice rapidly induces insulin resistance and glucose intolerance. Moreover, insulin resistance in obese humans is associated with a unique profile of IgG autoantibodies. These results establish the importance of B cells and adaptive immunity in insulin resistance and suggest new diagnostic and therapeutic modalities for managing the disease.
authors.affiliation: Department of Pathology, Stanford University, Palo Alto, California, USA. dan.winer@uhn.on.ca
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Winer
authors.forename: Shawn
authors.initials: S
authors.lastname: Winer
authors.forename: Lei
authors.initials: L
authors.lastname: Shen
authors.forename: Persis P
authors.initials: PP
authors.lastname: Wadia
authors.forename: Jason
authors.initials: J
authors.lastname: Yantha
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Paltser
authors.forename: Hubert
authors.initials: H
authors.lastname: Tsui
authors.forename: Ping
authors.initials: P
authors.lastname: Wu
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Davidson
authors.forename: Michael N
authors.initials: MN
authors.lastname: Alonso
authors.forename: Hwei X
authors.initials: HX
authors.lastname: Leong
authors.forename: Alec
authors.initials: A
authors.lastname: Glassford
authors.forename: Maria
authors.initials: M
authors.lastname: Caimol
authors.forename: Justin A
authors.initials: JA
authors.lastname: Kenkel
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Tedder
authors.forename: Tracey
authors.initials: T
authors.lastname: McLaughlin
authors.forename: David B
authors.initials: DB
authors.lastname: Miklos
authors.forename: H-Michael
authors.initials: HM
authors.lastname: Dosch
authors.forename: Edgar G
authors.initials: EG
authors.lastname: Engleman
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D004041:Dietary Fats / Q000009:adverse effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007148:Immunoglobulin mu-Chains / Q000235:genetics; D007249:Inflammation / Q000276:immunology; D007333:Insulin Resistance / Q000276:immunology*; D050152:Intra-Abdominal Fat / Q000276:immunology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D004041:Dietary Fats; D007074:Immunoglobulin G; D007148:Immunoglobulin mu-Chains; D005947:Glucose