Metabolic Flux Analysis of Obesity-Associated Inflammation in Weight Loss

减肥过程中肥胖相关炎症的代谢通量分析

• 批准号: 10202574
• 负责人: Jose Orlando Aleman
• 金额: $ 17.03万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-04 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10202574
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Adrenergic Agents; Affect; Anti-Inflammatory Agents; Bariatrics; Biological Models; Blood; Blood Cell Count; Body Weight decreased; Body fat; Breslow Thickness; Cell model; Cells; Chronology; Clinical; Coronary Arteriosclerosis; Cues; Data; Dental crowns; Detection; Development; Diabetes Mellitus; Diet; Disease; Dissociation; Exhibits; Fatty Acids; Fatty acid glycerol esters; Gastrectomy; Goals; Hallmark Cell; Heart Diseases; Heart failure; Human; Hyperglycemia; Immune; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Insulin Resistance; Intervention; Lead; Leukocytes; Link; Lipids; Lipolysis; Low income; Malignant Neoplasms; Manuscripts; Measures; Mentors; Metabolic; Metabolic Diseases; Metabolism; Minority; Modality; Modeling; Monocytosis; Nature; Necrosis; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Overweight; Patients; Phenotype; Population; Publishing; Research; Research Proposals; Risk Factors; Signal Pathway; Signal Transduction; Stimulus; Structure; Therapeutic; Tissues; United States; Universities; Weight; bariatric surgery; base; cardiometabolic risk; cardiovascular risk factor; cohort; diabetic; dietary; experience; extracellular; human subject; improved; indexing; inflammatory marker; insight; insulin sensitivity; lipid metabolism; lipidomics; macrophage; metabolomics; monocyte; obese person; obesity development; obesity prevention; prevent; programs; prospective; response; skills; systemic inflammatory response; therapeutic development; transcriptomics; translational study; ward

ABSTRACT Obesity is the most important preventable cause of disease in the United States, and its major complications include insulin resistance/type 2 diabetes, coronary artery disease (CAD), and heart failure. The reasons for these complications are not totally understood and assessment of patients before and after weight loss provides the opportunity to dissect the factors that are improved with reduced body fat. Elevated white blood cell (WBC) levels are a well-established CAD risk factor, while adipose tissue inflammation is considered an emerging risk factor for the development of obesity complications. However, the beneficial effects of weight loss on these inflammatory markers are not universal. Our recently published manuscript demonstrates how rapid diet-induced weight loss improves insulin sensitivity while increasing adipose tissue inflammation in human subjects. The proposed study will explore this dissociation and bariatric weight loss to seek mechanistic insight. We will characterize human adipose tissue macrophage metabolism in the context of weight loss using an in-vitro adipose tissue inflammation model (Aim 1). We will further assess changes in circulating WBC numbers and phenotype with bariatric weight loss in metabolically healthy versus unhealthy obese subjects undergoing sleeve gastrectomy (Aim 2), and concomitantly measure changes in adipose tissue inflammation (Aim 3) within six weeks of this intervention. The central hypothesis of this research is that lipid signals from the adipocyte modulate adipose tissue macrophage metabolism to prevent adipose tissue inflammation in weight loss. Consequently, the nature of this metabolic queue will prevent or ameliorate the WAT inflammatory state. Antiinflammatory macrophages are thought to maintain the integrity of healthy adipose tissue, while proinflammatory macrophages are thought to be the hallmark cell in adipose tissue inflammation. The rationale that underlies this research is that better understanding of the metabolic and immune cues that lead to white adipose tissue inflammation will allow for the development of detection and therapeutic strategies for this cardiometabolic risk factor. To achieve these aims, I will be supported by my primary mentor Dr. Ira Goldberg (NYULMC), a scientific leader in the study of lipid metabolism and circulating inflammatory markers in metabolic disease, and my co-mentor with expertise in the execution of detailed translational studies in the metabolic ward setting, Dr. Jan Breslow (Rockefeller University). Each mentor will help me complete the individual aims of this project and develop the skills to pursue my independent scientific program studying the immunometabolism of human adipose tissue during weight loss.

抽象的 肥胖是美国最重要的疾病原因，其主要并发症 包括胰岛素抵抗/2型糖尿病，冠状动脉疾病（CAD）和心力衰竭。原因 这些并发症尚未完全理解，减肥前后的患者评估 通过减少体内脂肪改善的因素的机会。升高的白细胞（WBC） 水平是公认的CAD危险因素，而脂肪组织炎症被认为是一种新兴的风险 肥胖并发症发展的因素。但是，减肥对这些的有益影响 炎症标记不是普遍的。我们最近出版的手稿证明了饮食诱导的速度 体重减轻可提高胰岛素敏感性，同时增加人类受试者的脂肪组织炎症。这 拟议的研究将探索这种分离和减肥体重减少以寻求机械洞察力。我们将 表征人类脂肪组织巨噬细胞代谢在体重减轻的背景下 脂肪组织炎症模型（AIM 1）。我们将进一步评估循环WBC数字的变化和 与袖子的不健康肥胖受试者相对于不健康的肥胖受试者的体重减轻的表型 胃切除术（AIM 2），并同时测量脂肪组织炎症的变化（AIM 3） 这项干预的几周。这项研究的中心假设是脂肪细胞调节的脂质信号 脂肪组织巨噬细胞代谢，以防止体重减轻时脂肪组织炎症。最后， 这种代谢队列的性质将预防或改善炎症状态。消炎（药 巨噬细胞被认为可以维持健康的脂肪组织的完整性，而促炎巨噬细胞 被认为是脂肪组织炎症中的标志性细胞。这项研究基础的理由是 更好地理解导致白脂肪组织炎症的代谢和免疫提示 允许为这种心脏代谢风险因素开发检测和治疗策略。实现 这些目标，我的主要导师伊拉·戈德堡（Ira Goldberg）博士（NYULMC）将为我提供支持，该研究的科学领导者 代谢疾病中的脂质代谢和循环炎症标志物以及我的专业知识 Jan Breslow博士（Rockefeller 大学）。每个导师将帮助我完成该项目的个人目标，并发展追求的技能 我的独立科学计划研究了体重减轻期间人脂肪组织的免疫代谢。