Metabolic Flux Analysis of Obesity-Associated Inflammation in Weight Loss

摘要 肥胖是美国最重要的可预防的疾病原因，其主要并发症 包括胰岛素抵抗/2型糖尿病、冠心病(CAD)和心力衰竭。原因是 这些并发症并不完全了解，对患者减肥前后的评估提供了 有机会剖析那些随着身体脂肪减少而改善的因素。白细胞升高(WBC) 水平是公认的冠心病危险因素，而脂肪组织炎症被认为是一个新的危险因素 肥胖并发症发生的因素。然而，减肥对这些人的有益影响 炎性标记物并不是通用的。我们最近发表的手稿展示了饮食诱导的快速 减肥改善了胰岛素敏感性，同时增加了受试者的脂肪组织炎症。这个 拟议的研究将探索这种分离和减肥，以寻求机制的洞察力。我们会 用体外实验研究减肥背景下人类脂肪组织巨噬细胞代谢的特征 脂肪组织炎症模型(目标1)。我们将进一步评估循环中的白细胞数量和 代谢性健康肥胖者与不健康肥胖者接受袖套治疗后体重减轻的表型 胃切除术(目标2)，同时测量6个月内脂肪组织炎症的变化(目标3 数周的干预行动。这项研究的中心假设是来自脂肪细胞的脂肪信号调节 脂肪组织巨噬细胞代谢可预防减肥中脂肪组织炎症。因此， 这种代谢队列的性质将防止或改善水的炎症状态。抗炎 巨噬细胞被认为维持健康脂肪组织的完整性，而促炎巨噬细胞 被认为是脂肪组织炎症的标志细胞。这项研究的基本原理是 更好地理解导致白色脂肪组织炎症的代谢和免疫信号将 考虑到对这种心脏代谢危险因素的检测和治疗策略的发展。要实现 为了实现这些目标，我将得到我的主要导师艾拉·戈德伯格博士的支持，他是这项研究的科学领导者 代谢性疾病的脂代谢和循环炎症标志物的研究，以及我的专家导师 在代谢病房环境下执行详细的翻译研究，Jan Breslow博士(Rockefeller 大学)。每一位导师将帮助我完成这个项目的个人目标，并培养我所追求的技能 我的独立科学计划，研究减肥期间人类脂肪组织的免疫代谢。

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.