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（T2 DM）是两种破坏性疾病，其患病率正在增长到流行病的比例。两者都与显著的发病率和死亡率水平相关;它们是非酒精性脂肪肝、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。此外，肥胖和T2 DM对患者及其亲人造成严重的情绪压力，每年造成数千亿美元的医疗保健支出。 肥胖的两个标志是血脂异常和胰岛素抵抗（IR），这强烈倾向于发展为T2 DM。然而，导致胰岛素作用降低和肥胖症中出现的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增加。在这个项目中，我们的目标是确定不仅巨噬细胞，但先天免疫的其他细胞，如树突状细胞，在肥胖的分子发病机制中的作用。我们将专注于肝脏的变化，因为肝脏是全身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，并且在肥胖症（即非酒精性脂肪性肝病）的情况下变得充满脂肪。 为了研究免疫细胞对肝脏代谢的影响，我们将利用共培养系统，使我们能够保持原代肝细胞接近单核细胞，但防止与单核细胞直接接触。我们将研究肝巨噬细胞（枯否细胞）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。 目前的T2 DM治疗方案旨在降低血清葡萄糖水平，但未解决伴随的炎症。这项研究将有助于阐明导致IR和T2 DM发展的病理生理学步骤。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发生IR和T2 DM。旨在预防T2 DM发作或逆转其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。 公共卫生相关性：肥胖症和II型糖尿病（diabesity）以及伴随的代谢异常（包括血脂异常、胰岛素抵抗和脂肪变性）的患病率在西方社会已达到接近流行病的比例。最近确定炎症作为这些代谢异常的一种贡献机制，为增加我们对糖尿病发病机制的理解和治疗方法的发展开辟了新的机会。完成本提案中详述的工作方案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.