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）：本提案涉及脂肪细胞/巨噬细胞脂肪酸结合蛋白（FABPs）的生物学作为一个模型实验系统，因为它们与肥胖的分子机制有关。FABPs是一个细胞质蛋白家族，在多种细胞类型中表达，并与脂肪酸、异种生物制剂和视黄酸结合。白色脂肪细胞和巨噬细胞共同表达两种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，改善了脂质代谢，并显著地保护了动脉粥样硬化。后者主要与aP2在巨噬细胞中的作用有关。mal1缺陷动物也表现出胰岛素敏感性适度升高和脂质代谢改变。最近，我们建立了一个缺乏aP2和mall （aP2-mal1-/-）的小鼠模型，以确定这些FABPs对全身代谢控制的影响。有趣的是，与单个FABP突变体不同，aP2- mal1-/-小鼠对体重增加和脂肪增加有抵抗力，并在高脂肪饮食中保持瘦体重，食物摄入量没有减少，但肌肉amp活化激酶（AMP-K）活性显著增加。在ob/ob模型中，减少的肥胖表型和AMP-K活性的增加消失了。然而，在初步研究中，ap2 -mal1缺陷小鼠可显著防止胰岛素抵抗和与饮食或遗传性肥胖相关的脂肪肝疾病。