The role of circulating meta-inflammatory monocytes in adolescent insulin resistance

循环元炎症单核细胞在青少年胰岛素抵抗中的作用

• 批准号: 10675006
• 负责人: Kanakadurga Singer
• 金额: $ 55.25万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10675006
• 关键词: Adolescent; Adolescent obesity; Adult; Animal Model; Animals; Antigen Presentation; Automobile Driving; CD14 gene; Cardiovascular Diseases; Cell Maturation; Cells; Child; Childhood; Clinical; Clinical Research; Data; Diabetes Mellitus; Diet; Dietary Fats; Dietary Fatty Acid; Disease; Eicosanoids; Ensure; Evaluation; Fatty Acids; Female; Female Adolescents; Flow Cytometry; Functional disorder; Future; Gene Expression; Glycosylated hemoglobin A; Hematopoietic; Heterogeneity; Human; Hypertriglyceridemia; ITGAX gene; Immune; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Knowledge; Leukocytes; Life; Link; Lipids; Lipopolysaccharides; Lymphocyte; Macrophage; Male Adolescents; Measures; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Modeling; Mus; Myelogenous; Myeloid Cells; Myelopoiesis; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Obesity; Outcome; Pathway interactions; Phenotype; Population; Prevalence; Production; Prostaglandins; Reproducibility; Risk; Risk Factors; Role; Saturated Fatty Acids; Sorting; TLR4 gene; Thinness; Tissues; Translating; United States; Vulnerable Populations; Weight; Woman; adult obesity; boys; clinically significant; cytokine; diabetes risk; disorder risk; fatty acid oxidation; girls; high risk; improved; in vivo; inflammatory marker; innovation; leukocyte activation; men; monocyte; obesogenic; preclinical study; predictive marker; prevent; progenitor; recruit; response; segregation; stem cells; trafficking; transcriptome sequencing; transcriptomics; translational approach; uptake

ABSTRACT Adults with obesity have increased myeloid inflammatory responses that associate with cardiovascular and metabolic disease. There are several gaps, though, in our current understanding of metabolic inflammation (meta-inflammation) including our understanding of initiating changes in myelopoiesis and regulated changes in myeloid cells. It is clear that some individuals develop a meta-inflammatory response placing them at higher risk for metabolic impairment while others are protected. While it is clinically important to identify adolescents at risk for future disease, we do not understand how to use meta-inflammatory markers to assess disease risk. Our previous human and mouse studies demonstrate that individuals who expand inflammatory monocytes in response to obesogenic diets are at greatest risk for metabolic disease. Based on the ability of these monocytes to generate an inflammatory response, traffic to tissues and differentiate into inflammatory tissue macrophages promoting insulin resistance, we are terming them meta-inflammatory monocytes (MiMo). Given that animal models and clinical studies have demonstrated that myeloid inflammation with circulating cytokines, enhanced circulating myeloid cells and tissue inflammation are linked with insulin resistance it is critical to understand if these same mechanisms exist in adolescents and can differentiate who is at risk for future metabolic disease. This proposal is based on the scientific premise that a diet high in saturated fatty acids (SFA) leads to myeloid leukocyte activation with expansion of myeloid progenitors, Ly6chi blood monocytes, and pro-inflammatory tissue macrophages leading to tissue dysfunction in animal studies. We propose the central hypothesis that adolescents at risk for metabolic disease have an increase in MiMos and enhanced MiMo recruitment, cytokine secretion and macrophage polarization leading to insulin resistance. We will evaluate this hypothesis in three aims: Aim 1) To define the monocyte transcriptomic signatures associated with metabolic disease in adolescents. Aim 2) To determine high risk and low risk monocyte phenotypes produced in adolescents with metabolic impairment. Aim 3) To assess meta-inflammatory monocyte activation and metabolism in response to dietary fatty acid stimulation. This proposal is innovative in the modeling and translational approach which is of high clinical significance. While the role of inflammation and metabolic disease has been studied over the last few decades little is known about this association in adolescents. This project will close the critical gap in translating pre-clinical studies on meta-inflammatory monocytes (MiMos) to adolescents. It will also investigate the mechanisms of disease risk through identification of detrimental monocyte phenotypes and the role of dietary fats in driving MiMo activation. These findings will lead to both biomarkers for prediction and pathways for intervention in pediatric metabolic disease.

摘要 肥胖成年人的髓系炎症反应增加，与心血管和 代谢性疾病。然而，在我们目前对代谢性炎症的理解中，有几个空白 (变态炎症)包括我们对骨髓生成启动变化和调节变化的理解 在髓系细胞中。很明显，一些人会产生一种元炎症反应，使他们处于较高的水平 在其他人受到保护的情况下，存在代谢损伤的风险。虽然在临床上识别青少年很重要 在未来疾病的风险中，我们不知道如何使用化炎性标记物来评估疾病风险。 我们之前的人类和小鼠研究表明，在体内扩张炎性单核细胞的个体 对肥胖饮食的反应是患代谢性疾病的最大风险。基于他们的能力 单核细胞产生炎症反应，运输到组织并分化为炎症组织 巨噬细胞促进胰岛素抵抗，我们称之为化炎性单核细胞(MIMO)。vt.给出 动物模型和临床研究已经证明，带有循环细胞因子的髓系炎症， 循环髓系细胞增强和组织炎症与胰岛素抵抗有关 了解这些相同的机制是否存在于青少年中，并可以区分谁是未来的风险人群 代谢性疾病。这一建议是基于这样一个科学前提，即高饱和脂肪酸饮食 (SFA)通过扩增髓系祖细胞、Ly6chi单核细胞、 在动物研究中，促炎症组织巨噬细胞导致组织功能障碍。我们建议 有代谢性疾病风险的青少年MIMO增加和增强的中心假设 MIMO募集、细胞因子分泌和巨噬细胞极化导致胰岛素抵抗。我们会 评估这一假设有三个目的：目的1)定义与单核细胞转录相关的信号 患有代谢性疾病的青少年。目的2)确定高危和低危单核细胞表型 在有代谢障碍的青少年中产生。目的3)评价化炎性单核细胞的活化 和新陈代谢对膳食脂肪酸刺激的反应。该方案在建模和分析方面具有创新性 具有较高临床意义的转化法。而炎症和代谢的作用 在过去的几十年里，人们一直在研究这种疾病，但对青少年中的这种联系知之甚少。这 该项目将填补将化炎性单核细胞(MIMOS)临床前研究转化为 青少年。它也将调查疾病风险的机制，通过识别有害的 单核细胞表型和饮食脂肪在驱动MIMO激活中的作用。这些发现将导致 儿科代谢性疾病的预测生物标志物和干预途径。