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: 10518047
• 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/10518047
• 关键词: Adolescent; Adolescent obesity; Adult; Animal Model; Animals; Antigen Presentation; Automobile Driving; Biological Markers; 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; ITGAX gene; Immune; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Intervention; Knowledge; Leukocytes; Life; Link; Lipids; Lipopolysaccharides; Lymphocyte; 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; RNA; Reproducibility; Risk; Risk Factors; Role; Saturated Fatty Acids; TLR4 gene; Thinness; Tissue Differentiation; Tissues; Translating; United States; Vulnerable Populations; Weight; adult obesity; base; boys; clinically significant; cytokine; diabetes risk; disorder risk; fatty acid oxidation; girls; high risk; improved; in vivo; inflammatory marker; innovation; leukocyte activation; macrophage; men; monocyte; obesogenic; preclinical study; prevent; progenitor; recruit; response; 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 患有肥胖症的成年人的骨髓炎症反应增加， 代谢性疾病然而，我们目前对代谢性炎症的理解存在一些差距 （元炎症）包括我们对骨髓生成的起始变化和调节变化的理解 在骨髓细胞中。很明显，有些人发展出一种元炎症反应，使他们处于更高的水平。 代谢障碍的风险，而其他人则受到保护。虽然在临床上识别青少年是很重要的 在未来疾病的风险，我们不知道如何使用元炎症标志物来评估疾病的风险。 我们以前的人类和小鼠研究表明，在炎症性单核细胞增多的个体， 对致胖饮食的反应是代谢疾病的最大风险。基于这些能力， 单核细胞产生炎症反应，运输到组织并分化成炎性组织 对于促进胰岛素抵抗的巨噬细胞，我们将其称为元炎性单核细胞（MiMo）。给定 动物模型和临床研究已经证明了具有循环细胞因子的骨髓炎症， 增强的循环骨髓细胞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 代谢性疾病这项建议是基于这样一个科学前提：高饱和脂肪酸的饮食 (SFA)导致骨髓白细胞活化，骨髓祖细胞，Ly6chi血单核细胞， 以及在动物研究中导致组织功能障碍的促炎组织巨噬细胞。我们建议 一个中心假设，即有代谢疾病风险的青少年的MiMos增加， 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 从三个方面评估这一假设：目的1）确定与单核细胞转录组相关的单核细胞转录组特征， 青少年代谢性疾病目的2）确定高危和低危单核细胞表型 代谢障碍的青少年中产生的。目的3）评估炎症性单核细胞活化 和代谢对膳食脂肪酸刺激的反应。该方案在建模上具有创新性， 翻译的方法，具有很高的临床意义。虽然炎症和代谢的作用 在过去的几十年里，人们对这种疾病进行了研究，但对青少年中的这种联系知之甚少。这 该项目将缩小将临床前研究转化为炎症性单核细胞（MiMos）的关键差距， 青少年。它还将通过识别有害的 单核细胞表型和膳食脂肪在驱动MiMo激活中的作用。这些发现将导致双方 用于预测的生物标志物和用于儿科代谢疾病干预的途径。