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A Role for B-1 B Cells and IgM Antibodies in Obesity-Induced Glucose Intolerance and Insulin Resistance

Harmon, Daniel
Thesis/Dissertation; Online
Harmon, Daniel
McNamara, Coleenn
Obesity, characterized by an excess of adipose tissue, is a leading cause of metabolic disease. It is now well accepted that obesity-induced adipose tissue inflammation contributes to systemic insulin resistance and glucose intolerance that can lead to type 2 diabetes. B cells and their secreted antibodies have recently emerged as important regulators of adipose tissue inflammation and insulin resistance associated with obesity, but roles for specific B cell subsets are still unclear. The helix-loop-helix factor Id3 mediates B cell function and obesity development, suggesting it may link B cells and metabolism. Here, we used a mouse containing a B cell-specific deletion of Id3 (Id3Bcell KO) to study the role B cells play in diet-induced adipose tissue inflammation and glucose intolerance. In addition, we assessed an obese human cohort for associations between adipose tissue B cells, natural IgM antibodies, and indices of inflammation and insulin resistance. Id3Bcell KO mice had increased numbers of visceral adipose tissue B-1b B cells and attenuated high-fat diet (HFD)-induced glucose intolerance compared to littermates. Omental visceral fat from Id3Bcell KO mice displayed enhanced local natural IgM secretion. Furthermore, Id3Bcell KO mice fed a short-term HFD had less inflammation and improved insulin signaling in omental fat compared to controls. Transfer of B-1b B cells null for Id3 was sufficient to attenuate diet-induced glucose intolerance in Rag1-/- hosts, while B-1b B cells unable to secrete IgM had no effect. In humans, a recently identified CD20+CD27+CD43+ B cell with B-1-like characteristics was identified within omental fat, and correlated with serum natural IgM levels. In addition, IgM antibodies were inversely associated with the inflammatory chemokine MCP-1 and insulin resistance. Results presented here provide the first evidence that IgM antibody-producing B-1b B cells attenuate diet-induced glucose intolerance in mice. In addition, we link anti-inflammatory natural IgM antibodies with reduced inflammation and improved metabolic phenotype in obese humans. Together, these findings suggest role for B-1 B cells and natural IgM antibodies in mediated obesity associated metabolic dysfunction.
Date Received
University of Virginia, Department of Biochemistry and Molecular Genetics, PHD (Doctor of Philosophy), 2014
Published Date
PHD (Doctor of Philosophy)
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