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: 7802865
• 负责人: XIAOLI CHEN
• 金额: $ 28.92万
• 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/7802865
• 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; 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; 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; public health relevance; 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（由申请人提供）：肥胖是发生胰岛素抵抗和代谢疾病的主要风险。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中起着关键作用。以脂肪因子/细胞因子的异常产生为特征的功能障碍性脂肪组织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/细胞因子介导这种联系以及肥胖过程中涉及的机制在很大程度上仍然未知。缺乏这方面的知识是一个关键问题，因为它是解决肥胖及其相关代谢综合征分子之谜的关键。我们的长期目标是阐明脂肪源性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，我们最近确定了脂质运载蛋白2（LCN 2）作为一个新的脂肪因子，可能连接肥胖和胰岛素抵抗。LCN 2属于脂质运载蛋白亚家族成员，其是与脂肪酸结合蛋白（FABP）具有结构相似性的小分泌蛋白，并且能够结合小疏水分子如FFA和视黄酸（RA）。LCN 2启动子具有NF-β B和C/EBP结合位点和糖皮质激素反应元件，LCN 2的分泌受LPS和TNF α的高度调节。在我们以前的研究中，LCN 2的表达水平在遗传性肥胖动物的脂肪组织和肝脏中上调。这种增加被TZD给药显著逆转。在3 T3- L1脂肪细胞中，LCN 2似乎增强胰岛素作用并拮抗TNF（对葡萄糖代谢、PPAR（基因表达和胰岛素抗性的影响）。此外，LCN 2抑制脂肪细胞以及巨噬细胞中TNF α和LPS诱导的细胞因子/趋化因子的产生。最引人注目的是，LCN 2调节脂肪细胞产生瘦素和脂联素。我们的研究结果导致的假设，LCN 2稳态调节炎症反应和胰岛素作用的脂肪细胞的负反馈调节机制，LCN 2缺乏导致促炎状态，脂肪分泌失调，并最终全身性胰岛素抵抗。我们进一步推测LCN 2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。该提议使用LCN 2缺失小鼠、LCN 2敲低的3 T3-L1脂肪细胞和缺乏配体结合能力的LCN 2突变体来测试三个特定目标。目的1研究LCN 2对炎症、胰岛素作用、脂肪细胞代谢和脂肪因子/细胞因子产生的调节。目的2定义LCN 2的配体结合和功能特性。目的3评估LCN 2缺乏对小鼠炎症反应、胰岛素作用和代谢稳态的影响。公共卫生关系： 越来越多的证据支持脂肪组织炎症、脂质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。该提案旨在确定和表征脂质运载蛋白2（一种新的脂肪衍生因子）在基于细胞的研究以及动物研究中调节炎症、胰岛素作用和脂肪细胞脂质/葡萄糖代谢的作用和机制。所获得的知识将为解决肥胖的分子难题提供关键，并导致确定预防和治疗干预的新策略。