Metabolic Crosstalk Between Immune Cells and the Liver in Obesity

描述（由申请人提供）：肥胖和2型糖尿病（T2DM）是两种破坏性疾病，其患病率正在上升至流行病的比例。两者都与高水平的发病率和死亡率有关；它们是导致非酒精性脂肪性肝病、失明、肾衰竭和非创伤性截肢的主要原因，这些患者患心血管疾病的风险也在增加。此外，肥胖和2型糖尿病会给患者及其亲人造成严重的情绪压力，每年的医疗支出高达数千亿美元。肥胖的两个标志是血脂异常和胰岛素抵抗（IR），这两种疾病都容易导致2型糖尿病的发生。然而，导致胰岛素作用下降和肥胖代谢紊乱的生化和分子机制仍不完全清楚。最近的研究表明炎症增加，特别是巨噬细胞数量和活性升高。在这个项目中，我们的目标是确定巨噬细胞，以及其他先天免疫细胞，如树突状细胞，在肥胖的分子发病机制中的作用。我们将重点关注肝脏的变化，因为肝脏是全身性碳水化合物和脂质代谢的关键调节剂，是胰岛素的主要靶点，具有自身广泛的常驻免疫系统，并且在肥胖（即非酒精性脂肪肝）的情况下充满脂肪。为了研究免疫细胞对肝脏代谢的影响，我们将利用一种共培养系统，该系统允许我们将原代肝细胞保持在靠近单核细胞的位置，但防止与单核细胞直接接触。我们将研究肝巨噬细胞（Kupffer细胞）和树突状细胞对肝细胞脂质代谢和胰岛素作用的影响，并确定这些影响的机制。目前T2DM的治疗方案旨在降低血糖水平，但不解决伴随的炎症。这项研究将有助于阐明导致IR和T2DM发展的病理生理步骤。更好的机制知识将允许开发新的治疗方法，这不仅可以降低疾病的严重程度，还可以预防肥胖个体的IR和T2DM的发展。旨在预防发病或逆转2型糖尿病病因的治疗最有可能降低发病率和死亡率，并改善患者的生活质量。

DESCRIPTION (provided by applicant): Obesity and type 2 diabetes mellitus (T2DM) are two devastating diseases that are growing in prevalence to epidemic proportions. Both are associated with significant levels of morbidity and mortality; they are leading causes of non-alcoholic fatty liver disease, blindness, kidney failure and non-traumatic amputations, and these patients are also at increased risk for cardiovascular disease. Additionally, obesity and T2DM cause significant emotional strain on the patient and their loved ones, and account for hundreds of billions of dollars in health care expenditures each year. Two hallmarks of obesity are dyslipidemia and insulin resistance (IR), which strongly predispose to the development of T2DM. However, the biochemical and molecular mechanisms that cause decreased insulin action and the metabolic disturbances seen in obesity remain incompletely understood. Recent work has implicated increased inflammation, specifically elevated macrophage numbers and activity. In this project, we aim to determine the role of not only macrophages, but other cells of innate immunity, e.g. dendritic cells, in the molecular pathogenesis of obesity. We will be concentrating on changes in the liver, since the liver is a critical modulator of systemic carbohydrate and lipid metabolism, is a primary target of insulin, has its own extensive, resident immune system, and becomes engorged with fat in the setting of obesity (i.e. non-alcoholic fatty liver disease). To study the effects of immune cells on liver metabolism, we will be utilizing a co-culture system which allows us to maintain primary hepatocytes in close proximity to, but preventing direct contact with, mononuclear cells. We will investigate the effects of liver macrophages (Kupffer cells) and dendritic cells on hepatocyte lipid metabolism and insulin action and determine the mechanisms of these effects. Current treatment regimens for T2DM aim to lower serum glucose levels but do not address the concomitant inflammation. This research will help elucidate the pathophsyiologic steps leading to the development of IR and T2DM. Better mechanistic knowledge will allow the development of new treatments, which may not only reduce the severity of disease but also prevent the development of IR and T2DM in obese individuals. Therapy aimed at preventing the onset or reversing the cause of T2DM would most likely decrease morbidity and mortality and improve patients' quality of life. PUBLIC HEALTH RELEVANCE: The prevalence of obesity and type II diabetes (diabesity), and attendant metabolic abnormalities including dyslipidemia, insulin resistance, and steatosis has reached near epidemic proportions in western societies. The recent identification of inflammation as a contributory mechanism to these metabolic abnormalities has opened up new opportunities for increasing our understanding of the pathogenesis of diabesity and the development of treatments. The completion of the work program detailed in this proposal has the potential to influence both of these areas.