Metabolic Crosstalk Between Immune Cells and the Liver in Obesity

描述(申请人提供)：肥胖和2型糖尿病(T2 DM)是两种破坏性的疾病，其患病率正在上升到流行的比例。两者都与显著的发病率和死亡率有关；它们都是非酒精性脂肪肝、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增加了。此外，肥胖和2型糖尿病会给患者及其亲人带来巨大的情感压力，每年的医疗保健支出高达数千亿美元。肥胖的两个特征是血脂异常和胰岛素抵抗(IR)，这两个特征极易导致T2 DM的发生。然而，导致胰岛素作用减弱和肥胖症代谢障碍的生化和分子机制仍然不完全清楚。最近的研究表明炎症增加，特别是巨噬细胞数量和活性增加。在这个项目中，我们的目标不仅是确定巨噬细胞，而且还有其他天然免疫细胞，例如树突状细胞，在肥胖的分子发病机制中所起的作用。我们将专注于肝脏的变化，因为肝脏是全身碳水化合物和脂肪代谢的关键调节器，是胰岛素的主要靶点，拥有自己广泛的常驻免疫系统，并且在肥胖(即非酒精性脂肪性肝病)的背景下变得充斥着脂肪。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，使原代肝细胞保持在接近单个核细胞的位置，但防止与单个核细胞直接接触。我们将研究肝巨噬细胞(Kupffer细胞)和树突状细胞对肝细胞脂代谢和胰岛素作用的影响，并确定这些作用的机制。目前T2 DM的治疗方案旨在降低血糖水平，但不能解决伴随而来的炎症。这项研究将有助于阐明导致IR和T2 DM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，这不仅可以减轻疾病的严重程度，还可以防止肥胖者发展为IR和T2 DM。旨在预防或逆转T2 DM发病原因的治疗极有可能降低发病率和死亡率，改善患者的生活质量。 与公共卫生相关：在西方社会，肥胖和II型糖尿病(糖尿病)以及随之而来的代谢异常(包括血脂异常、胰岛素抵抗和脂肪变性)的患病率已接近流行水平。最近发现炎症是导致这些代谢异常的一种机制，这为我们进一步了解糖尿病的发病机制和治疗方法的发展提供了新的机会。本提案中详细说明的工作计划的完成有可能对这两个领域产生影响。

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.