Lipocalin 2 in Inflammation and Metabolic Control

脂质运载蛋白 2 在炎症和代谢控制中的作用

• 批准号: 8049105
• 负责人: XIAOLI CHEN
• 金额: $ 28.41万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049105
• 关键词: Adipocytes; Adipose tissue; Agonist; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Bacterial Infections; Binding; Binding Sites; Biological Process; Blood Circulation; CCAAT-Enhancer-Binding Proteins; Cells; Chronic; Defect; Development; Endocrine; Endocrine Glands; Energy Metabolism; Fatty Acids; Feedback; Functional disorder; Gene Expression; Glucocorticoids; Goals; Health; Homeostasis; Immune; Immune response; In Vitro; Inflammation; Inflammation Mediators; Inflammatory Response; Insulin; Insulin Resistance; Knockout Mice; Knowledge; Lead; Leptin; Ligand Binding; Link; Lipids; Liver; Mediating; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Peroxisome Proliferator-Activated Receptors; Play; Preventive Intervention; Production; Property; Proteins; Proteomics; Regulation; Response Elements; Risk; Role; Screening procedure; Source; TNF gene; Testing; Therapeutic Intervention; Tissues; Tretinoin; adipokines; adiponectin; base; chemokine; cytokine; fatty acid-binding proteins; glucose metabolism; macrophage; member; mutant; novel strategies; promoter; receptor

DESCRIPTION (provided by applicant): Obesity is a major risk for developing insulin resistance and metabolic diseases. Adipose tissue plays a critical role as an endocrine organ and a major source of chronic low-grade inflammation in the regulation of insulin action and energy metabolism. Dysfunctional adipose tissue characterized by abnormal production of adipokines/cytokines has been linked to obesity and its associated inflammation, insulin resistance, and metabolic dysregulation. However, which adipokines/cytokines mediate this linkage and the mechanisms involved during obesity remain largely unknown. Lack of such knowledge is a critical problem as it is the key to solve the molecular puzzle of obesity and its related metabolic syndrome. Our long-term goal is to elucidate the role and mechanisms of adipose-derived factors in the regulation of inflammation and metabolic homeostasis. Through the proteomics and microarray screening, we recently identified lipocalin 2 (LCN2) as a new adipokine that potentially connects obesity and insulin resistance. LCN2 belongs to the lipocalin subfamily members that are small secreted proteins with a structural similarity to fatty acid binding proteins (FABPs) and the ability to bind small hydrophobic molecules such as FFA and retinoic acid (RA). LCN2 promoter possesses NF-(B and C/EBP binding sites and glucocorticoid response element; and LCN2 secretion is highly regulated by LPS and TNF(. In our previous studies, the level of LCN2 expression is up-regulated in adipose tissue and liver of genetically obese animals. This increase is significantly reversed by TZD administration. LCN2 appears to potentiate insulin action and antagonize TNF( effects on glucose metabolism, PPAR( gene expression and insulin resistance in 3T3- L1 adipocytes. Moreover, LCN2 suppresses TNF(- and LPS-induced cytokine/chemokine production in adipocytes as well as macrophages. Most strikingly, LCN2 regulates the adipocyte production of leptin and adiponectin. Our results lead to the hypothesis that LCN2 homeostatically regulates inflammatory response and insulin action in adipocytes by a negative feedback regulatory mechanism, and that LCN2 deficiency causes a proinflammatory state, dysregulation of adipose secretion, and ultimately systemic insulin resistance. We further hypothesize that LCN2 exerts its biological functions in adipocytes via the ligand binding and receptor-mediated transport mechanism. This proposal uses LCN2 null mice, LCN2 knockdown 3T3-L1 adipocytes, and mutants of LCN2 that lack ligand binding ability to test three specific aims. Aim 1 investigates the regulation of LCN2 in inflammation, insulin action, adipocyte metabolism, and adipokine/cytokine production. Aim 2 defines the ligand binding and functional properties of LCN2. Aim 3 assesses the impact of LCN2 deficiency on inflammatory response, insulin action, and metabolic homeostasis in mice. PUBLIC HEALTH RELEVANCE: Increasing evidence supports the role of adipose tissue inflammation, lipid metabolic defects, and endocrine dysfunction in obesity and insulin resistance. This proposal aims at identifying and characterizing the role and mechanism of lipocalin 2, a new adipose-derived factor, in the regulation of inflammation, insulin action, and adipocyte lipid/glucose metabolism in cell-based as well as animal studies. The knowledge obtained will provide the key to solve the molecular puzzle of obesity and lead to the identification of novel strategies for preventive and therapeutic interventions.

描述(申请人提供)：肥胖是发展胰岛素抵抗和代谢性疾病的主要风险。脂肪组织作为内分泌器官和慢性低度炎症的主要来源，在调节胰岛素作用和能量代谢方面起着关键作用。功能失调的脂肪组织以脂肪因子/细胞因子的异常产生为特征，与肥胖及其相关的炎症、胰岛素抵抗和代谢失调有关。然而，哪些脂肪因子/细胞因子介导了这种联系，以及肥胖过程中涉及的机制在很大程度上仍不清楚。缺乏这样的知识是一个关键问题，因为这是解决肥胖及其相关代谢综合征的分子之谜的关键。我们的长期目标是阐明脂肪衍生因子在炎症和代谢稳态调节中的作用和机制。通过蛋白质组学和微阵列筛选，我们最近发现Lipocalin 2(Lcn2)是一种新的脂肪因子，可能与肥胖和胰岛素抵抗有关。Lcn2属于Lipocalin亚家族成员，是一种结构类似于脂肪酸结合蛋白(FABP)的小分泌蛋白，具有结合FFA和维甲酸(RA)等疏水小分子的能力。Lcn2启动子具有NF-(B和C/EBP)结合部位和糖皮质激素反应元件，其分泌受内毒素和肿瘤坏死因子的高度调控。在我们之前的研究中，Lcn2在遗传性肥胖动物的脂肪组织和肝脏中的表达水平上调。这种增加被TZD管理显着逆转。Lcn2可增强胰岛素作用，拮抗肿瘤坏死因子对3T3-L1脂肪细胞糖代谢、PPAR基因表达和胰岛素抵抗的影响。此外，Lcn2抑制由肿瘤坏死因子和脂多糖诱导的脂肪细胞和巨噬细胞的细胞因子/趋化因子的产生。最引人注目的是，Lcn2调节脂肪细胞产生瘦素和脂联素。我们的结果导致假设，Lcn2通过负反馈调节机制对脂肪细胞的炎症反应和胰岛素作用进行动态平衡调节，Lcn2缺乏会导致促炎状态，脂肪分泌失调，最终导致全身性胰岛素抵抗。我们进一步假设Lcn2通过配体结合和受体介导的转运机制在脂肪细胞中发挥其生物学功能。这项建议使用Lcn2基因缺失的小鼠、Lcn2基因敲除的3T3-L1脂肪细胞和缺乏配体结合能力的Lcn2突变基因来测试三个特定的靶点。目的1研究Lcn2在炎症、胰岛素作用、脂肪细胞代谢和脂肪因子/细胞因子产生中的调节作用。目的2定义Lcn2的配体结合和功能性质。目的3评价Lcn2缺乏对小鼠炎症反应、胰岛素作用和代谢稳态的影响。公共卫生相关性： 越来越多的证据支持脂肪组织炎症、脂代谢缺陷和内分泌功能障碍在肥胖和胰岛素抵抗中的作用。本研究旨在鉴定和表征一种新的脂肪衍生因子--Lipocalin 2在细胞和动物研究中对炎症、胰岛素作用和脂肪细胞脂/糖代谢的调节作用和机制。所获得的知识将为解决肥胖症的分子谜团提供关键，并导致确定预防和治疗干预的新策略。