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