Regulation of adipose cells by autotaxin / lysophosphatidic acid signaling

通过自分泌运动因子/溶血磷脂酸信号传导调节脂肪细胞

• 批准号: 8198376
• 负责人: Susan S. Smyth
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198376
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Affect; American; Animal Model; Attention; Attenuated; Behavior Therapy; Body Weight decreased; Body mass index; Brown Fat; Cardiovascular system; Caring; Cell surface; Consumption; Data; Deposition; Desire for food; Development; Diet; Disease; Down-Regulation; Energy Metabolism; Exhibits; Family; Fatty acid glycerol esters; G-Protein-Coupled Receptors; Gap Junctions; Generations; Genetic; Goals; Grant; Health; Healthcare; Heating; Human; In Vitro; Integral Membrane Protein; Investigation; Knowledge; Lipids; Liquid substance; Lysophospholipids; Medical center; Molecular; Mus; Names; Obesity; Organism; Overweight; Plasma; Play; Positioning Attribute; Prevention; Production; Protein Dephosphorylation; Reagent; Recombinants; Regulation; Reporting; Research; Role; Signal Pathway; Signal Transduction; System; Techniques; Testing; Therapeutic; Thermogenesis; Tissue Differentiation; United States; Veterans; Weight Gain; Work; abstracting; adipocyte biology; adipocyte differentiation; alkylglycerophosphoethanolamine phosphodiesterase; extracellular; functional status; improved; in vivo; inhibitor/antagonist; innovation; lipid phosphate phosphatase; lysophosphatidic acid; member; novel; obesity prevention; obesity treatment; overexpression; precursor cell; prevent; public health relevance; tool; transdifferentiation

DESCRIPTION (provided by applicant): Project Summary/Abstract Obesity and obesity-related cardiovascular complications are an increasing health burden in the United States. An analysis of nearly 2 million veterans receiving care at VA Medical Centers in 2000 indicated that ~68% were overweight and ~37% were obese. Despite extensive investigation, viable therapeutic strategies to prevent weight gain or promote weight loss remain largely elusive. Attention has recently focused on the exciting possibility that a therapeutic strategy aimed at promoting energy expenditure by increasing brown adipose tissue (BAT) content or activity in adults could reduce fat deposition and obesity. However, such a therapeutic strategy requires a comprehensive understanding of factors that regulate BAT. Lysophosphatidic acid (LPA) is a bioactive lipid present in physiologically relevant levels in plasma and other biologic fluids and is positioned to play a role in human health and disease. The secreted lysophospholipase D autotaxin (autotaxin/lysoLPD) is responsible for production of extracellular, biologically active LPA, which is in turn inactivated by enxymatic dephosphorylation by lipid phosphate phosphatases (LPP). We provide evidence that treatment of primary cultures of preadipocytes with LPA or autotaxin reduces expression of markers of brown adipocyte differentiation and LPP3, an endogenous regulator of Wnt; whereas a novel autotaxin/lysoPLD inhibitor dramatically promotes brown adipocyte differentiation. In mice, overexpression of autotaxin reduces UCP1 expression and promotes diet-induced obesity. We therefore propose the central hypothesis that signaling pathways regulated by autotaxin and LPP3 contribute to diet-induced thermogenesis and regulate the development of diet-induced obesity. We will test our central hypothesis using state-of-the art genetic and pharmacologic approaches in three specific aims. In Aim One, we will identify the role of autotaxin/lysoPLD in regulation of brown adipose tissue and diet-induced obesity in animal models. In Aim Two, we will establish the molecular mechanism(s) by which LPA and autotaxin exert their effects. In Aim Three, we identify the role of LPP3 in development and function of adipose tissue and diet-induced obesity. The aims of this grant provide a vehicle to address a major unresolved issue in the field of lysolipid signaling, namely role of autotaxin/lysoPLD, LPA, and LPP3 in regulation of adiposity. These results will be significant, because they are expected to provide innovative targets and provide proof-of-concept for novel inhibitors that may be used for prevention and treatment of obesity in humans. PUBLIC HEALTH RELEVANCE: Project Narrative More than 44 million Americans are obese, as defined by body mass index (BMI) of >30 kg/m2. Obesity is a significant health care problem among veterans receiving care at VA Medical Centers. A comprehensive analysis of nearly 2 million veterans in 2000 indicated that ~68% were overweight and ~37% were obese. Current strategies to treat and prevent obesity focus primarily on reducing energy consumption through appetite suppression and behavioral modification. Recent attention has focused on an attractive alternative approach, namely that of increasing energy expenditure by enhancing the heat-dissipating function of brown adipose tissue in adults. We provide evidence that the secreted lysophospholipase D autotaxin, responsible for production of biologically active LPA, may regulate the functional status of brown adipose tissue. The goal of the current study is to identify the role of the autotaxin/LPA signaling nexus in the regulation of adipose tissue and diet-induced obesity. Our results may suggest innovative targets to prevent and treat obesity in humans.

描述（由申请人提供）： 肥胖和肥胖相关的心血管并发症是美国日益增加的健康负担。2000年，一项对在退伍军人医疗中心接受治疗的近200万退伍军人的分析表明，约68%的人超重，约37%的人肥胖。尽管进行了广泛的研究，但预防体重增加或促进体重减轻的可行治疗策略在很大程度上仍然难以捉摸。最近人们的注意力集中在一种令人兴奋的可能性上，即旨在通过增加成人棕色脂肪组织（BAT）含量或活性来促进能量消耗的治疗策略可以减少脂肪沉积和肥胖。然而，这种治疗策略需要全面了解调节BAT的因素。溶血磷脂酸（LPA）是一种生物活性脂质，在血浆和其他生物液体中以生理相关水平存在，并在人类健康和疾病中发挥作用。分泌的溶血磷脂酶D自分泌运动因子（自分泌运动因子/lysoLPD）负责细胞外生物活性LPA的产生，其进而通过脂质磷酸磷酸酶（LPP）的酶解去磷酸化而失活。我们提供的证据表明，用LPA或自分泌运动因子处理前脂肪细胞的原代培养物可降低棕色脂肪细胞分化标志物和Wnt内源性调节因子LPP 3的表达;而一种新的自分泌运动因子/lysoPLD抑制剂可显著促进棕色脂肪细胞分化。在小鼠中，autotaxin的过度表达降低了UCP 1的表达，并促进了饮食诱导的肥胖。因此，我们提出了中心假设，即自分泌运动因子和LPP 3调节的信号通路有助于饮食诱导的产热，并调节饮食诱导的肥胖症的发展。我们将使用最先进的遗传学和药理学方法在三个具体目标中测试我们的中心假设。在目的一中，我们将确定autotaxin/lysoPLD在调节棕色脂肪组织和饮食诱导的肥胖动物模型中的作用。目的二是建立LPA和autotaxin发挥作用的分子机制。在目的三中，我们确定LPP 3在脂肪组织和饮食诱导的肥胖的发育和功能中的作用。这项资助的目的是提供一种工具来解决溶血脂质信号传导领域中一个主要的未解决的问题，即自分泌运动因子/lysoPLD，LPA和LPP 3在肥胖调节中的作用。这些结果将是重要的，因为它们有望提供创新的靶点，并为可用于预防和治疗人类肥胖的新型抑制剂提供概念验证。 公共卫生相关性： 超过4400万美国人肥胖，定义为身体质量指数（BMI）>30 kg/m2。肥胖是退伍军人在VA医疗中心接受治疗的一个重要的医疗保健问题。2000年对近200万退伍军人的综合分析表明，约68%的人超重，约37%的人肥胖。目前治疗和预防肥胖的策略主要集中在通过抑制食欲和行为改变来减少能量消耗。最近的注意力集中在一个有吸引力的替代方法，即通过提高成人棕色脂肪组织的散热功能来增加能量消耗。我们提供的证据表明，分泌的溶血磷脂酶D自分泌运动因子，负责生产的生物活性LPA，可能会调节棕色脂肪组织的功能状态。本研究的目的是确定autotaxin/LPA信号通路在调节脂肪组织和饮食诱导的肥胖中的作用。我们的研究结果可能为预防和治疗人类肥胖提供创新靶点。