IgG and Adipose Pathological Remodeling

项目摘要 肥胖是许多高度流行的合并症的原因，如胰岛素抵抗，2型糖尿病， 心血管疾病（CVD）、血脂异常、肝脏疾病和癌症-所有这些都是不可或缺的 与脂肪组织病理学有关。脂肪组织对代谢健康至关重要， 肥胖症的病理变化，包括慢性炎症、脂肪生成减少、纤维化和受损 代谢功能在这里，PI建议测试一种非传统的机制来整合脂肪组织 肥胖的病理变化。他证明了免疫球蛋白G（IgG）的明显积累， 在衰老和饮食诱导的肥胖（DIO）小鼠的白色脂肪组织（WAT）中，而热量限制（1）， 对代谢功能障碍最有效的干预，特别是减少脂肪IgG。IgG是主要的 是一类抗体，传统上被视为免疫防御的循环蛋白。施用 瘦小鼠中的外源性IgG模拟肥胖，具有WAT富集分布，损害胰岛素敏感性， 诱导脂肪组织炎症。通过敲除（KO）唯一的IgG来消耗全身的IgG 骨髓细胞中的再循环蛋白FcRn（FcRnflox/flox：LysM-Cre，FcRn-mKO）可预防高脂饮食诱导的体重 增重、脂肪组织炎症和纤维化以及代谢功能障碍。此外，从治疗 从另一个角度来看，通过反义寡核苷酸（阿索）靶向FcRn抑制IgG积累，改善FcRn的表达。 脂肪形成和棕色重塑，并恢复DIO小鼠的代谢功能。IgG直接治疗 诱导脂肪细胞前体中的炎症和纤维化基因，并抑制PPARg， 因子，导致脂肪生成受损。因此，他假设IgG是一个关键因素，推动了 肥胖症中WAT的病理性重塑和代谢功能障碍，以及FcRn依赖性再循环是 这是其在WAT中异常积累所必需的。通过结合小鼠的遗传、生化、细胞和 分子方法，他将通过以下具体目标来严格检验这一假设。目标1：首先 了解IgG如何在肥胖症中优先在WAT中积累。在WAT中，FcRn主要是 在脂肪基质细胞（ASC，Pdgfra+）和脂肪细胞中表达。因此，他有条件地敲 在ASC（FcRnflox/flox：Pdgfra-Cre，FcRn-pKO）和脂肪细胞（FcRnflox/flox：Adipoq-Cre，FcRn-aKO）中的FcRn。他 将剖析它们各自对脂肪IgG积累和病理重塑的贡献。他将 进一步确定它们对肥胖症中代谢功能障碍和全身IgG稳态的影响。在目标2中， 他将阐明IgG通过Toll样受体4损害脂肪功能的分子机制 （TLR 4）/PPARg轴。总之，拟议的工作将确定IgG作为适应不良的致病因素 的WAT在肥胖症，从而提供了一种机制，整合了肥胖WAT的特点。揭开 脂肪IgG积累中FcRn的需求将激发通过靶向IgG的新的治疗策略 回收来恢复肥胖症患者的代谢健康。

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.