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.

项目总结 肥胖是导致许多高度普遍的并发症的原因，如胰岛素抵抗、2型糖尿病、 心血管疾病、血脂异常、肝病和癌症--所有这些都是不可或缺的 与脂肪组织病理学有关。脂肪组织对新陈代谢健康至关重要，并经历了 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 新陈代谢功能。在这里，PI建议测试一种非传统的整合脂肪组织的机制 肥胖的病理变化。他表现出明显的免疫球蛋白G(IgG)积累，尤其是 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)， 对代谢功能障碍最有效的干预措施，特别是降低脂肪免疫球蛋白。免疫球蛋白是主要的 抗体的一类，传统上被视为免疫防御的循环蛋白。管理 瘦小鼠体内的外源性免疫球蛋白类似于肥胖症，富含Wat，降低胰岛素敏感性，并 导致脂肪组织发炎。通过敲除(KO)唯一的免疫球蛋白来消耗全身的免疫球蛋白 髓系细胞循环蛋白FcRN(FcRnflx/Flox：LysM-Cre，FcRN-MKO)预防高脂饮食诱导的体重 体重增加、脂肪组织炎症和纤维化以及代谢功能障碍。此外，从一个治疗性的 前景：通过反义寡核苷酸(ASO)靶向FcRN抑制免疫球蛋白积聚，改善 脂肪生成和棕色重塑，并恢复DIO小鼠的代谢功能。直接免疫球蛋白治疗 诱导脂肪细胞前体细胞中的炎症和纤维化基因并抑制终极成脂因子PPARg 因素，导致脂肪生成受阻。因此，他假设免疫球蛋白是推动 肥胖症患者WAT的病理重塑和代谢功能障碍，以及FcRN依赖的循环 在水中异常堆积所需的。通过将小鼠的遗传、生化、细胞和 分子方法，他将通过以下具体目标批判性地检验这一假说。在目标1中，他将首先 了解肥胖症患者体内的免疫球蛋白是如何优先积聚的。在WAT中，FcRN主要是 在脂肪基质细胞(ASCs，PDGFRA+)和脂肪细胞中表达。因此，他有条件地敲门 FcRnFLOX/FLOX：PDGFRA-CRE，FcRN-PKO)和脂肪细胞(FcRnFLOX/FLOX：ADIPOQ-CRE，FcRN-Ako)。他 将剖析它们各自在脂肪免疫球蛋白蓄积和病理重塑中的作用。他会的 进一步确定它们对肥胖患者代谢紊乱和全身免疫球蛋白稳态的影响。在目标2中， 他将阐明免疫球蛋白通过Toll样受体4损害脂肪功能的分子机制 (TLR4)/PPARg轴。总之，拟议的工作将确定免疫球蛋白是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 FcRN在脂肪免疫球蛋白蓄积中的要求将通过靶向免疫球蛋白激发新的治疗策略 回收以恢复肥胖患者的新陈代谢健康。