IgG and Adipose Pathological Remodeling

IgG 和脂肪病理重塑

• 批准号: 10564224
• 负责人: Anthony W Ferrante
• 金额: $ 48.42万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-06 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564224
• 关键词: Address; Adipocytes; Adipose tissue; Aging; Antibodies; Antisense Oligonucleotides; Automobile Driving; Biochemical; Biological Response Modifiers; Caloric Restriction; Cardiovascular Diseases; Cells; Chronic; Data; Dependence; Development; Drug or chemical Tissue Distribution; Dyslipidemias; Fibrosis; Functional disorder; Genes; Half-Life; Health; High Fat Diet; Homeostasis; Hypertrophy; Immune; Immunoglobulin G; Immunologic Factors; Impairment; Inflammation; Inflammatory; Insulin Resistance; Knock-out; Knockout Mice; Label; Ligands; Light; Liver diseases; LoxP-flanked allele; MADH3 gene; Malignant Neoplasms; Mediator; Medical; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Modeling; Molecular; Mus; Myeloid Cells; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathologic; Pathology; Peroxisome Proliferator-Activated Receptors; Phenotype; Prevention; Production; Proteins; Recycling; Repression; Role; Signal Transduction; Stromal Cells; TLR2 gene; TLR4 gene; Testing; Therapeutic; Thinness; Tissues; Virulence Factors; Weight Gain; Work; comorbidity; conditional knockout; diet-induced obesity; effective intervention; energy balance; improved; in vitro Model; in vivo; insight; insulin sensitivity; lipid biosynthesis; mouse genetics; neonatal Fc receptor; novel; novel therapeutic intervention; overexpression; prevent; progenitor; stem cells

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.

项目概要 肥胖是导致许多高度普遍的合并症的原因，例如胰岛素抵抗、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 与脂肪组织病理有关。脂肪组织对于代谢健康至关重要，并且经历显着的变化 肥胖的病理变化，包括慢性炎症、脂肪生成减少、纤维化和受损 代谢功能。 PI 在此提议测试一种非常规机制来整合脂肪组​​织 肥胖的病理变化。他展示了免疫球蛋白 G (IgG) 的明显积累，特别是 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)， 针对代谢功能障碍最有效的干预措施，特别是降低脂肪 IgG。 IgG为主 一类抗体，传统上被视为免疫防御的循环蛋白。管理 瘦小鼠中的外源 IgG 模仿肥胖，并在 WAT 中分布丰富，损害胰岛素敏感性，并且 诱发脂肪组织炎症。通过敲除 (KO) 唯一的 IgG 来耗尽全身的 IgG 骨髓细胞中的回收蛋白 FcRn（FcRnflox/flox:LysM-Cre、FcRn-mKO）可预防高脂肪饮食引起的体重 增益、脂肪组织炎症和纤维化以及代谢功能障碍。此外，从治疗 从长远来看，通过反义寡核苷酸（ASO）靶向 FcRn 可抑制 IgG 积累，改善 脂肪生成和棕色重塑，并恢复 DIO 小鼠的代谢功能。直接进行IgG治疗 诱导脂肪细胞前体细胞中的炎症和纤维化基因并抑制 PPARg（最终的脂肪形成因子） 因素，导致脂肪生成受损。因此，他推测 IgG 是驱动该疾病的关键因素。 WAT 的病理重塑和肥胖中的代谢功能障碍，以及 FcRn 依赖性回收 其在WAT中异常积累所必需的。通过结合小鼠遗传、生化、细胞和 通过分子方法，他将通过以下具体目标批判性地检验这一假设。在目标 1 中，他首先会 了解肥胖症患者 IgG 如何优先积聚在 WAT 中。在 WAT 中，FcRn 主要是 在脂肪基质细胞（ASC、Pdgfra+）和脂肪细胞中表达。所以他有条件敲了 在 ASC (FcRnflox/flox:Pdgfra-Cre, FcRn-pKO) 和脂肪细胞 (FcRnflox/flox:Adipoq-Cre, FcRn-aKO) 中去除 FcRn。他 将剖析它们各自对脂肪 IgG 积累和病理重塑的贡献。他会 进一步确定它们对肥胖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 (TLR4)/PPARg 轴。总之，拟议的工作将确定 IgG 作为适应不良的致病因素 WAT 在肥胖中的作用，从而提供了一种整合肥胖 WAT 特征的机制。揭开 脂肪 IgG 积累中 FcRn 的需求将激发一种通过靶向 IgG 的新治疗策略 回收以恢复肥胖症的代谢健康。