B cell mechanisms underlie IgG glycan alterations in obesity.

Insulin resistance is a major complication of obesity. In adults with obesity insulin resistance is associated with a hyposialylation of the Fc-linked glycan on IgG, and a causal link between IgG hyposialylation and glucose dysregulation has been demonstrated in obese mice. What is unknown is how obesity causes the changes in IgG glycosylation. To avoid factors besides obesity that may influence IgG glycosylation, we sought to fill this knowledge gap by studying adolescents with and without obesity. We demonstrate that in pediatric obesity IgG is hyposialylated and hypogalactosylated, with the changes most apparent in females, and that this is related to an upregulation of B cell WNT3, a GWAS-identified candidate gene for IgG glycosylation whose function in glycan modulation was previously unknown. In parallel, WNT3 is upregulated in B cells from obese mice. Linkage between WNT3 upregulation and decreased IgG galactosylation and sialylation was demonstrated in both a HEK293FS cell model and an ARH-77 B lymphoblast cell line. These observations indicate that obesity causes IgG hypogalactosylation and resulting hyposialylation by previously unrecognized actions of WNT3 which regulate IgG galactosylation in B cells. Better understanding of how obesity alters the unique glycobiology of IgG offers the possibility of identifying additional therapeutic targets in the battle against the insulin resistance that complicates obesity.