IgG and Adipose Pathological Remodeling

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PROJECT SUMMARY Obesity is responsible for numerous, highly prevalent comorbidities such as insulin resistance, type 2 diabetes, cardiovascular diseases (CVDs), dyslipidemia, liver diseases, and cancers - all of which are indispensably related to adipose tissue pathologies. Adipose tissue is vital for metabolic health and undergoes pronounced pathological changes in obesity, including chronic inflammation, decreased adipogenesis, fibrosis, and impaired metabolic function. Here the PI proposes to test an unconventional mechanism to integrate adipose tissue pathological changes in obesity. He demonstrates a stark accumulation of immunoglobulin G (IgG) particularly in white adipose tissues (WAT) in both aging- and diet-induced obese (DIO) mice, whereas caloric restriction (1), the most effective intervention against metabolic dysfunctions, specifically reduces adipose IgG. IgG is the major class of antibodies and is traditionally viewed as a circulating protein for immune defense. Administering exogenous IgG in lean mice mimics obesity with an enriched distribution to WAT, impairs insulin sensitivity, and induces adipose tissue inflammation. Depleting IgG in the whole body by knocking out (KO) the sole IgG recycling protein FcRn in myeloid cells (FcRnflox/flox:LysM-Cre, FcRn-mKO) prevents high fat diet-induced weight gain, adipose tissue inflammation and fibrosis, and metabolic dysfunctions. Furthermore, from a therapeutic perspective, targeting FcRn by antisense oligonucleotides (ASO) inhibits IgG accumulation, improves adipogenesis and brown remodeling, and restores metabolic functions in DIO mice. IgG treatment directly induces inflammatory and fibrotic genes in adipocyte precursors and represses PPARg, the ultimate adipogenic factor, resulting in impaired adipogenesis. Therefore, he hypothesizes that IgG is a critical factor that drives the pathological remodeling of WAT and metabolic dysfunctions in obesity, and FcRn-dependent recycling is required for its abnormal accumulation in WAT. By combining mouse genetic, biochemical, cellular, and molecular approaches, he will critically test this hypothesis by the following specific aims. In Aim 1, he will first understand how IgG is preferentially accumulated in WAT in obesity. Within WAT, FcRn is predominantly expressed in adipose stromal cells (ASCs, Pdgfra+) and adipocytes. Therefore, he has conditionally knocked out FcRn in ASCs (FcRnflox/flox:Pdgfra-Cre, FcRn-pKO) and adipocytes (FcRnflox/flox:Adipoq-Cre, FcRn-aKO). He will dissect their respective contributions to adipose IgG accumulation and pathological remodeling. He will further determine their effects on metabolic dysfunctions and whole-body IgG homeostasis in obesity. In Aim 2, he will elucidate a molecular mechanism by which IgG impairs adipose functions through a Toll-like receptor 4 (TLR4)/PPARg axis. In summary, the proposed work will identify IgG as a pathogenic factor in the maladaptation of WAT in obesity, thereby providing a mechanism that integrates the hallmarks of obese WAT. Uncovering the requirement of FcRn in adipose IgG accumulation will incite a novel therapeutic strategy through targeting IgG recycling to restore metabolic health in obesity.