Lipids, Inflammation and Insulin Action

脂质、炎症和胰岛素作用

• 批准号: 6827062
• 负责人: GOKHAN S HOTAMISLIGIL
• 金额: $ 45.83万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6827062
• 关键词: adenosine monophosphate; adenylate kinase; adipocytes; bioenergetics; biological models; body weight; cell differentiation; cell type; collagen; complement; dietary lipid; enzyme activity; fatty acid binding protein; gene expression; genetic models; inflammation; insulin; insulin sensitivity /resistance; laboratory mouse; leptin; lipid metabolism; lipids; macrophage; molecular pathology; nutrition related tag; obesity; pathologic process; protein protein interaction; protein structure function

DESCRIPTION (provided by applicant): This proposal deals with biology of adipocyte/macrophage fatty acid binding proteins (FABPs) as a model experimental system as they relate to the molecular mechanisms of obesity. FABPs are a family of cytoplasmic proteins expressed in a variety of cell types and bind to fatty acids, xenobiotics and retinoic acid. White adipocytes and macrophages co-express two FABP isoforms, aP2 and mal1, which have critical functions in both metabolic and inflammatory responses. Mice lacking aP2 have reduced insulin resistance associated with obesity, improved lipid metabolism and dramatically protected from atherosclerosis. The latter is predominantly related to the action of aP2 in macrophages. Mal1-deficient animals also exhibit moderately increased insulin sensitivity and altered lipid metabolism. Recently, we developed a mouse model lacking both aP2 and mall (aP2-mal1-/-) to determine the impact of these FABPs on systemic metabolic control. Interestingly, and unlike the individual FABP mutants, the aP2- mal1-/- mice are resistant to weight gain and increased adiposity and maintained their lean body mass on a high fat diet with no reduction in food intake but a significant increase in muscle AMP-activated kinase (AMP-K) activity. In the ob/ob model, the reduced adiposity phenotype and the increase in AMP-K activity are lost. However, in preliminary studies, aP2-mal1-deficient mice were dramatically protected against insulin resistance and fatty liver disease associated with either dietary or genetic obesity. We propose to study the impact of aP2-mal1-combined deficiency in detail with respect to adipogenesis and obesity using dietary and genetic (leptin-deficient) models. We will address the target cell types involved in this action of FABPs and address the potential involvement of macrophages. We will also address the role of AMP-kinase activation in muscle as a mechanism of increased fatty acid utilization, energy expenditure and weight reduction and test the sensitivity of peripheral organs to adipocyte-derived hormones leptin and adiponectin in the presence and absence of FABPs. We will develop additional experimental systems to generate insights into the mechanisms of action of aP2 and mal1, identify protein interactions with these FABPs in their target cells and study the pathways underlying their biology with respect to obesity. The adipocyte/macrophage fatty acid binding proteins play a central role in obesity and the associated disorders in mice and provide an outstanding tool to study the underlying mechanisms to many key components of the metabolic syndrome. The proposed studies will provide important insights regarding the mechanisms by which FABPs integrate inflammatory and metabolic pathways regulate systemic energy homeostasis.

描述（由申请人提供）：该建议涉及脂肪细胞/巨噬细胞脂肪酸结合蛋白（FABP）的生物学，作为模型实验系统，因为它们与肥胖的分子机制有关。 Fabps是一种以多种细胞类型表达的细胞质蛋白家族，并与脂肪酸，异种生物和视黄酸结合。白色脂肪细胞和巨噬细胞共表达两种FABP同工型AP2和MAL1，它们在代谢和炎症反应中具有关键功能。缺乏AP2的小鼠降低了与肥胖相关的胰岛素抵抗，改善脂质代谢，并受到极大的保护，免受了动脉粥样硬化。后者主要与AP2在巨噬细胞中的作用有关。 MAL1缺陷动物还表现出适度提高胰岛素敏感性并改变了脂质代谢。最近，我们开发了一种缺乏AP2和MALL（AP2-MAL1 - / - ）的小鼠模型来确定这些Fabps对系统性代谢控制的影响。有趣的是，与单个FABP突变体不同，AP2-MAL1 - / - 小鼠具有对体重增加和肥胖性增加的抵抗力，并在高脂肪饮食上保持瘦体重，而不会减少食物摄入量，但会显着增加肌肉AMP激活激活激酶（AMP-K）活性。在OB/OB模型中，减少的肥胖表型和AMP-K活性的增加丢失了。然而，在初步研究中，AP2-MAL1缺陷型小鼠受到极大的保护，免受与饮食或遗传肥胖相关的胰岛素抵抗和脂肪肝疾病。 我们建议使用饮食和遗传（瘦素缺陷型）模型详细研究AP2-MAL1综合缺乏症对脂肪生成和肥胖的影响。我们将解决该作用的目标细胞类型，并解决巨噬细胞的潜在参与。我们还将解决AMP-激酶在肌肉中的作用，这是增加脂肪酸利用，能量消耗和减轻体重的机制，并测试外周科器官对脂肪细胞衍生的激素瘦素和脂肪蛋白在存在和不存在Fabps的情况下的敏感性。我们将开发其他实验系统，以产生对AP2和MAL1作用机理的见解，在其靶细胞中识别与这些FABP的蛋白质相互作用，并研究其生物学对肥胖的途径。脂肪细胞/巨噬细胞脂肪酸结合蛋白在肥胖症和小鼠中相关疾病中起着核心作用，并为研究代谢综合征的许多关键成分提供了出色的工具。拟议的研究将提供有关FABP整合炎症和代谢途径调节全身能量稳态的机制的重要见解。