Leptin Action and Macrophages

瘦素作用和巨噬细胞

• 批准号: 8104928
• 负责人: ROBERT M O'DOHERTY
• 金额: $ 44.63万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8104928
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Address; Adipocytes; Area; Biochemical; Cells; Chronic; Coculture Techniques; Data; Development; Diet; Dyslipidemias; Epidemic; Funding; Hepatic; Hepatocyte; Homeostasis; Hormones; Human; Inflammation; Inflammatory Response; Insulin; Insulin Resistance; Kupffer Cells; Leptin; Leptin resistance; Lipids; Liver; Macrophage Activation; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Molecular; Molecular Analysis; Mus; Myeloid Cells; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Organ; Overnutrition; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Play; Prevalence; Process; Regulation; Role; Societies; System; Tissues; Very low density lipoprotein; Work; base; energy balance; human FRAP1 protein; insight; insulin sensitivity; lipid metabolism; macrophage; novel; prevent; programs; release factor

DESCRIPTION (provided by applicant): The actions of the adipocyte-derived hormone leptin on lipid metabolism are proposed to be important in preventing the development of tissue lipotoxicity and lipid-related insulin resistance. This is best illustrated in leptin-deficient states, where chronic administration of exogenous leptin corrects systemic dyslipidemia, excessive storage of lipid in peripheral tissues such as the liver, and insulin resistance associated with this condition. Furthermore, states of leptin resistance such as human obesity and diet-induced obesity (DIO) are characterized by a similar metabolic phenotype to leptin deficient conditions, implicating a role for a loss of leptin action in the pathogenesis of the metabolic abnormalities of obesity. However, despite some progress, our understanding of the mechanisms of leptin regulation of lipid metabolism and insulin action, and the mechanisms of leptin resistance remains poor. Our work over the last decade has focused on the effects and mechanisms of leptin action on lipid metabolism and insulin sensitivity, with our recent work focusing on liver, a central organ in the regulation of whole-body lipid homeostasis and insulin sensitivity. In brief these studies established a novel role for leptin in the acute regulation of hepatic oxidative and VLDL metabolism, effects that are impaired in obesity, and identified the biochemical basis for these effects. In preliminary data, we present evidence that many of these effects are mediated by specialized liver macrophages (Kupffer cells). These data demonstrate a previously unappreciated role for myeloid cells in mediating the metabolic actions of leptin. The central objective of the current proposal is to extend these observations to address (i) the role of macrophages in mediating the metabolic actions of leptin, and (ii) the biochemical and molecular mechanisms of macrophage leptin action. In undertaking these studies, we will increase our understanding of the mechanisms of leptin action and the contribution of leptin resistance to the metabolic abnormalities of obesity. To address these questions we will utilize a range of models, including genetically manipulated mice and cell based co-culture systems, and approaches, including metabolic, biochemical, and molecular analysis. 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. Leptin, the adipocyte hormone, has been proposed to play a role in the regulation of each of these processes. Thus, an understanding of the mechanisms and targets of leptin action are critical to delineating the pathogenesis of, and the development of potential treatments for, diabesity. The completion of the work program detailed in this proposal has the potential to influence both of these areas.

描述（由申请人提供）：脂肪细胞衍生激素瘦素对脂质代谢的作用被认为在预防组织脂毒性和脂质相关胰岛素抵抗的发展中是重要的。这在瘦素缺乏状态中得到最好的说明，其中长期施用外源性瘦素纠正全身性血脂异常、脂质在外周组织（如肝脏）中的过度储存以及与这种状况相关的胰岛素抵抗。此外，瘦素抵抗状态如人肥胖和饮食诱导的肥胖（DIO）的特征在于与瘦素缺乏病症相似的代谢表型，暗示瘦素作用丧失在肥胖代谢异常的发病机制中的作用。然而，尽管取得了一些进展，我们对瘦素调节脂质代谢和胰岛素作用的机制以及瘦素抵抗的机制的理解仍然很差。在过去的十年里，我们的工作集中在瘦素对脂质代谢和胰岛素敏感性的作用和机制上，我们最近的工作集中在肝脏，一个调节全身脂质稳态和胰岛素敏感性的中心器官。总之，这些研究确立了瘦素在肝脏氧化和VLDL代谢的急性调节中的新作用，这些作用在肥胖症中受损，并确定了这些作用的生化基础。在初步数据中，我们提出的证据表明，许多这些影响是由专门的肝脏巨噬细胞（枯否细胞）介导的。这些数据表明，以前未得到重视的作用，骨髓细胞介导的代谢活动的瘦素。目前建议的中心目标是扩展这些观察，以解决（i）巨噬细胞在介导瘦素代谢作用中的作用，以及（ii）巨噬细胞瘦素作用的生化和分子机制。通过这些研究，我们将加深对瘦素作用机制以及瘦素抵抗对肥胖代谢异常的作用的理解。为了解决这些问题，我们将利用一系列模型，包括遗传操作的小鼠和基于细胞的共培养系统，以及方法，包括代谢，生物化学和分子分析。 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。瘦素，脂肪细胞激素，已被提出发挥作用，在每个这些过程的调节。因此，了解瘦素作用的机制和靶点对于阐明糖尿病的发病机制和潜在治疗方法的发展至关重要。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。