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; 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.

抽象的 肥胖的成年人增加了与心血管和心血管和 代谢疾病。但是，在我们目前对代谢炎症的理解中有几个差距 （元炎），包括我们对骨髓病的变化的理解和规范的变化 在髓样细胞中。显然，有些人会产生元炎症反应，使他们处于更高的状态 代谢损害的风险，而其他人则受到保护。虽然识别青少年在临床上很重要 有未来疾病的风险，我们不了解如何使用元炎症标记来评估疾病风险。 我们以前的人类和小鼠研究表明，扩展炎症单核细胞的个体 对肥胖饮食的反应是代谢疾病的最大风险。基于这些的能力 单核细胞产生炎症反应，对组织交通并分化为炎症组织 巨噬细胞促进胰岛素抵抗，我们正在称它们为元炎性单核细胞（MIMO）。给出 动物模型和临床研究表明，循环细胞因子的髓样炎症， 增强的循环髓样细胞和组织炎症与胰岛素抵抗有关，这对于 了解这些相同的机制是否存在于青少年中，并且可以区分谁有未来的风险 代谢疾病。该提议基于以下科学前提：饱和脂肪酸的饮食 （SFA）随着髓样祖细胞的膨胀Ly6chi血单核细胞的膨胀导致髓样白细胞激活 和促炎性组织巨噬细胞导致动物研究中组织功能障碍。我们建议 中心假设是，有代谢疾病风险的青少年有含羞道的增加并增强了 MIMO募集，细胞因子分泌和巨噬细胞极化导致胰岛素抵抗。我们将 在三个目的中评估这一假设：目标1）定义与单核细胞转录组相关的特征 青少年的代谢疾病。目标2）确定高风险和低风险单核细胞表型 在有代谢障碍的青少年生产。目标3）评估元炎性单核细胞激活 以及响应饮食脂肪酸刺激的代谢。该建议在建模和 翻译方法具有很高的临床意义。而炎症和代谢的作用 在过去的几十年中，对疾病的研究对青少年的这种关联知之甚少。这 项目将缩小对元炎性单核细胞（MIMO）的临床前研究的关键差距 青少年。它还将通过鉴定有害的疾病风险机理 单核细胞表型和饮食脂肪在驱动MIMO激活中的作用。这些发现将导致两者 预测和干预小儿代谢疾病的途径的生物标志物。