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: 9892484
• 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/9892484
• 关键词: Acute; Address; Adipocytes; Adipose tissue; Adrenergic Agents; Affect; Anti-Inflammatory Agents; Anti-inflammatory; 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; experience; extracellular; human subject; improved; indexing; inflammatory marker; insight; insulin sensitivity; lipid metabolism; macrophage; metabolomics; monocyte; obesity development; prevent; programs; prospective; response; skills; 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.

摘要