Lipids, Inflammation and Insulin Action

描述（由申请人提供）：本提案涉及脂肪细胞/巨噬细胞脂肪酸结合蛋白（FABPs）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。FABP是在多种细胞类型中表达的细胞质蛋白家族，并与脂肪酸、外源性物质和视黄酸结合。白色脂肪细胞和巨噬细胞共表达两种FABP亚型aP 2和mal 1，其在代谢和炎症反应中具有关键功能。缺乏aP 2的小鼠降低了与肥胖相关的胰岛素抵抗，改善了脂质代谢，并显着防止动脉粥样硬化。后者主要与巨噬细胞中aP 2的作用有关。Mal 1缺陷动物也表现出适度增加的胰岛素敏感性和改变的脂质代谢。最近，我们开发了一种缺乏aP 2和mall的小鼠模型（aP 2-mal 1-/-），以确定这些FABP对全身代谢控制的影响。有趣的是，与单个FABP突变体不同，aP 2-mal 1-/-小鼠对体重增加和肥胖增加有抵抗力，并在高脂肪饮食中保持其瘦体重，食物摄入量没有减少，但肌肉AMP激活激酶（AMP-K）活性显著增加。在ob/ob模型中，减少的肥胖表型和AMP-K活性的增加丢失。然而，在初步研究中，aP 2-mal 1缺陷小鼠显着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（瘦素缺乏）模型详细研究aP 2-mal 1-联合缺乏对脂肪形成和肥胖的影响。我们将讨论参与FABPs这一作用的靶细胞类型，并讨论巨噬细胞的潜在参与。我们还将讨论肌肉中AMP激酶激活的作用，作为增加脂肪酸利用、能量消耗和减轻体重的机制，并测试外周器官在存在和不存在FABP的情况下对脂肪细胞衍生激素瘦素和脂联素的敏感性。我们将开发额外的实验系统，以深入了解aP 2和mal 1的作用机制，确定蛋白质与靶细胞中这些FABP的相互作用，并研究其生物学与肥胖相关的途径。脂肪细胞/巨噬细胞脂肪酸结合蛋白在小鼠肥胖及其相关疾病中起着核心作用，并为研究代谢综合征许多关键组分的潜在机制提供了出色的工具。拟议的研究将提供重要的见解有关的机制，FABP整合炎症和代谢途径调节全身能量稳态。

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.