AUTHOR=Kim Sohyun , Kim Junghyun , Lee Hyung-Lae , Kim Man S. 

TITLE=Temporal dynamics of IgG-mediated immunometabolic dysfunction: from acute obesity to chronic aging

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1661391

DOI=10.3389/fimmu.2025.1661391

ISSN=1664-3224

ABSTRACT=Immunoglobulin G (IgG) is traditionally recognized as a circulating immune effector; however, recent discoveries have revealed that IgG accumulates in adipose tissue—up to 16-fold above plasma levels—and functions as a critical mediator of metabolic dysfunction in obesity and aging. This review summarizes evidence showing that adipocyte IgG accumulation occurs via neonatal Fc receptor (FcRn)-mediated uptake and directly competes with insulin for receptor binding through Fc-CH3 domain interactions. IgG initiates tissue-specific inflammatory responses. Functional outcomes depend on glycosylation patterns: sialylated IgG (e.g., control IgG) signals anti-inflammatory pathways via DC-SIGN and CD22, whereas hyposialylated IgG (e.g., disease-associated IgG) activates endothelial FcγRIIB receptors, impairs insulin transcytosis, and promotes vascular insulin resistance. This mechanism may help explain the limited success of conventional anti-inflammatory treatments for metabolic diseases. The timeline of IgG-mediated effects progresses through acute inflammation (weeks), subacute deposition and insulin interference (months), and chronic fibrosis (years). Notably, FcRn antagonists can reverse insulin resistance, while restoration of IgG sialylation using sialic acid precursors improves function without depleting antibodies. These findings suggest that IgG dysfunction occurs at the intersection of obesity, aging, and metabolic disease, offering new biomarkers and therapeutic targets. Glycosylation profiling enables the discrimination between insulin-sensitive and -resistant individuals with similar body mass indices, supporting precision medicine approaches. This paradigm shift, from cell-centric to antibody-mediated models, reframes our understanding of metabolic disease pathogenesis and offers novel treatment strategies.