B Cell Mechanisms Underlie IgG Glycan Alterations in Obesity

ABSTRACT: The glycosylation of B cell-derived IgG is altered in the setting of obesity, and it contributes to obesity-related insulin resistance. With obesity in both humans and mice a key glycan on the Fc region of IgG is deficient in galactose and in the terminal sialic acid that is linked to galactose. How obesity causes the changes in IgG glycosylation has been unknown. Here we report studies of circulating IgG and B cells from adolescents who are lean, obese without type 2 diabetes (T2D), or obese with T2D. Mirroring prior reports we demonstrate that in obesity IgG is hyposialylated and hypogalactosylated, with the changes most apparent in females. B cell transcriptomes were evaluated by RNA-seq on cells from 4 female subjects in each of the 3 study group. RNA-seq and quantitative PCR reveal that the changes in IgG glycosylation are related to a decline in B cell B4GALT1 expression and an upregulation of B cell WNT3, which is a GWAS-based candidate gene for the regulation of IgG glycosylation. In parallel, B4GALT1 is downregulated and WNT3 is upregulated in B cells from obese mice, and mechanistic linkage between WNT3 upregulation and B4GALT1 downregulation and altered IgG glycosylation was demonstrated in a HEK293FS cell model. Thus, obesity causes IgG hyposialylation by altering mechanisms regulating 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE270270 | GEO | 2026/09/23

REPOSITORIES: GEO