Lipids, Inflammation and Insulin Action

描述(申请人提供)：这项提案涉及脂肪细胞/巨噬细胞脂肪酸结合蛋白(FABP)的生物学，作为一个模型实验系统，因为它们与肥胖的分子机制有关。FABP是一个细胞质蛋白家族，在各种细胞类型中表达，并与脂肪酸、外源化合物和维甲酸结合。白色脂肪细胞和巨噬细胞共表达两种FABP亚型，aP2和Mal1，这两种亚型在代谢和炎症反应中都具有关键功能。缺乏aP2的小鼠减少了与肥胖相关的胰岛素抵抗，改善了脂代谢，并显著保护了免受动脉粥样硬化的影响。后者主要与aP2在巨噬细胞中的作用有关。Mal1基因缺陷的动物也表现出适度的胰岛素敏感性增加和脂代谢改变。最近，我们建立了一种同时缺乏aP2和MALL(aP2-Mal1-/-)的小鼠模型，以确定这些FABP对全身代谢控制的影响。有趣的是，与单个FABP突变体不同的是，aP2-Mal1/-小鼠对体重增加和肥胖增加具有抵抗力，并在高脂肪饮食中保持其精瘦的身体质量，食物摄入量没有减少，但肌肉AMP-K活性显著增加。在ob/ob模型中，肥胖减少的表型和AMP-K活性的增加丢失。然而，在初步研究中，aP2-Mal1缺陷小鼠在胰岛素抵抗和与饮食或遗传肥胖相关的脂肪肝疾病方面得到了显著保护。 我们建议使用饮食和遗传(瘦素缺乏)模型，详细研究aP2-Mal1联合缺乏对脂肪形成和肥胖的影响。我们将讨论FABP这一作用中涉及的靶细胞类型，并讨论巨噬细胞的潜在参与。我们还将探讨肌肉中AMP-激酶的激活作为增加脂肪酸利用、能量消耗和体重减轻的机制，并测试在FABPs存在和不存在的情况下，外围器官对脂肪细胞衍生激素瘦素和脂联素的敏感性。我们将开发更多的实验系统，以深入了解aP2和Mal1的作用机制，确定在其靶细胞中与这些FABP的蛋白质相互作用，并研究它们与肥胖相关的生物学途径。脂肪细胞/巨噬细胞脂肪酸结合蛋白在小鼠肥胖和相关疾病中起着核心作用，为研究代谢综合征许多关键成分的潜在机制提供了出色的工具。这项拟议的研究将为FABP整合炎症和代谢途径调节全身能量稳态的机制提供重要的见解。

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.