A Role for B-1 B Cells and IgM Antibodies in Obesity-Induced Glucose Intolerance and Insulin Resistance 1116 views

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.

PHD (Doctor of Philosophy)

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2014-07-01