Adipose Macrophage Iron Handling

脂肪巨噬细胞铁处理

• 批准号: 10624942
• 负责人: Alyssa H Hasty
• 金额: $ 50.09万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10624942
• 关键词: Adipocytes; Adipose tissue; Affect; Bioenergetics; Biogenesis; Bone Marrow; Cells; Contracts; DNA; DNA biosynthesis; Data; Dependence; Disease; Dose; Environment; Epidemic; Erythrocytes; Erythropoiesis; Exposure to; Fasting; Ferritin; Free Radicals; Gene Expression; Genes; Glucose Clamp; Haptoglobins; Health; Hemoglobin; Homeostasis; Hyperinsulinism; Impairment; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Innate Immune System; Insulin; Iron; Iron Isotopes; Iron Overload; Iron-Dextran Complex; Kupffer Cells; Laboratories; Lipids; Liposomes; Literature; Macrophage; Metabolic; Mitochondria; Mus; Nutrient; Obesity; Pathway interactions; Phenotype; Physiological; Prevention; Production; Proliferating; Property; Proteins; Publications; Recycling; Respiration; Role; Serum; Signal Transduction; TFRC gene; Thinness; Tissue Expansion; Tissues; Work; adipocyte differentiation; arm; blood glucose regulation; cell type; diabetes risk; diet-induced obesity; environmental enrichment for laboratory animals; glucose tolerance; hemoglobin/haptoglobin receptor; holotransferrin; insulin sensitivity; iron metabolism; lipid biosynthesis; metabolomics; metal transporting protein 1; oxidative damage; senescence; tissue repair; transcriptome sequencing

Systemic control of iron mobilization serves two main functions: to provide iron for erythropoiesis and to deplete iron during bacteriostasis. Yet, every cell in the body requires iron – for respiration, DNA synthesis, and proliferation; while iron-overload can lead to oxidative damage to proteins, DNA, and lipid. Thus, iron concentrations at the tissue and cellular level must be exquisitely controlled by mechanisms that compliment and fine-tune systemic control. Reticuloendothelial Mϕs are distinctly suited to recycle Fe from senescent erythrocytes by their high expression of CD163, the hemoglobin/haptoglobin receptor, which is uniquely expressed on M2-like Mϕs. Our over-arching hypothesis is that tissue macrophages (Mϕs) are “ferrostats”, sensing and responding to local tissue iron needs. This role of Mϕs is particularly important in adipose tissue (AT); sufficient levels are required for adipogenesis in this tissue that must expand and contract more rapidly than any other tissue, and prevention of free radical production is particularly important in a lipid-enriched environment. Mϕs are not simply cells of the innate immune system that are critical defenders against infection. In fact, they reside in all tissues and show remarkable plasticity based upon their local environment. This plasticity requires rapid polarization on a spectrum of phenotypes ranging from M1-like inflammatory to M2-like tissue repair phenotypes. We have identified a unique subpopulation of ATMϕs that have an iron-recycling phenotype and are highly M2-polarized1. Furthermore, we show that these specialized Mϕs take up excess iron, protecting the adipocytes from iron overload2. We refer to these iron cycling ATMϕs as MFehi and the remaining ATMϕs as MFelo. MFehi Mϕs express high levels of iron-related genes such as CD163, transferrin receptor (TfR1), and the iron exporter, ferroportin (Fpn). While our MFehi cells express some M2 genes, we have intriguing preliminary data showing that MFehi bioenergetics are different than M2 bioenergetics, suggesting that AT MFehi cells are uniquely polarized. Premised on our data, we hypothesize that: proper iron handling creates a uniquely polarized ATMϕ phenotype that enhances their ability to influence adipogenesis and insulin action in AT. In our three aims, we will determine the extent to which: 1) Mϕ iron processing influences polarization and intrinsic immunometabolism, 2) ATMϕ iron handling impacts adipocyte differentiation, insulin sensitivity and AT expansion, 3) Dysregulated ATMϕ polarization and iron handling contribute to AT health and systemic insulin action during nutrient excess.

铁动员的系统控制有两个主要功能：为红细胞生成提供铁，并使红细胞生成