Protective Role for B-1b B Cells and IgM in Obesity-Associated Inflammation, Glucose Intolerance, and Insulin Resistance

Authors:
  • DHDaniel B Harmon
    Daniel B Harmon
  • JKJennifer L Kaplan
    Jennifer L Kaplan
  • SOStephanie N Oldham
    Stephanie N Oldham
  • CMChantel McSkimming
    Chantel McSkimming
  • JGJames C Garmey
    James C Garmey
  • HPHeather M Perry
    Heather M Perry
  • JKJennifer L Kirby
    Jennifer L Kirby
  • AGAyelet Gonen
    Ayelet Gonen
  • PHPeter Hallowell
    Peter Hallowell
  • BSBruce Schirmer
    Bruce Schirmer
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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. Approach and 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.

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