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: 8043979
• 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/8043979
• 关键词: Address; Adipocytes; Adipose tissue; Adult; Affect; Animal Model; Attention; Attenuated; Body Weight decreased; Brown Fat; Cardiovascular system; Caring; Cell surface; Data; Deposition; Development; Diet; Disease; Down-Regulation; Energy Metabolism; Exhibits; Family; Fatty acid glycerol esters; G-Protein-Coupled Receptors; Gap Junctions; Generations; Genetic; Goals; Grant; Health; 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; improved; in vivo; inhibitor/antagonist; innovation; lipid phosphate phosphatase; lysophosphatidic acid; member; novel; obesity prevention; obesity treatment; overexpression; precursor cell; prevent; 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)： 项目摘要/摘要肥胖和肥胖相关的心血管并发症在美国是一个日益严重的健康负担。一项对2000年在退伍军人医疗中心接受护理的近200万退伍军人的分析表明，~68%的退伍军人超重，~37%的退伍军人肥胖。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，即一种旨在通过增加成年人棕色脂肪组织(BAT)含量或活动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，这样的治疗策略需要对调节BAT的因素有全面的了解。溶血磷脂酸(LPA)是一种生物活性脂质，存在于血浆和其他生物体液中的生理相关水平，在人类健康和疾病中发挥着重要作用。分泌的溶血磷脂酶D自体趋化蛋白(Autoaxin/lysoLPD)负责产生细胞外具有生物活性的LPA，而LPA又被脂磷酸盐磷酸酶(LPP)的酶促去磷酸化失活。我们提供的证据表明，用LPA或自体趋化素处理原代培养的前脂肪细胞可以减少棕色脂肪细胞分化的标志物和WNT的内源性调节因子LPP3的表达；而一种新的自体趋化因子/溶解PLD抑制剂显著促进棕色脂肪细胞的分化。在小鼠中，过度表达的自体趋化蛋白减少了UCP1的表达，并促进了饮食诱导的肥胖。因此，我们提出了一个中心假设，即由自体趋化蛋白和LPP3调控的信号通路有助于饮食诱导的产热，并调控饮食诱导肥胖的发展。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上测试我们的中心假设。在第一个目标中，我们将在动物模型中确定自体趋化蛋白/溶解PLD在调节棕色脂肪组织和饮食诱导的肥胖中的作用。在第二个目标中，我们将建立LPA和自体趋化蛋白发挥作用的分子机制(S)。在第三个目标中，我们确定了LPP3在脂肪组织的发育和功能以及饮食诱导的肥胖中的作用。这项资助的目的是提供一种工具来解决溶脂信号领域中一个尚未解决的主要问题，即自体趋化蛋白/溶菌素磷脂酶D、LPA和LPP3在调节肥胖中的作用。这些结果将是重要的，因为它们有望提供创新的靶点，并为可能用于预防和治疗人类肥胖症的新型抑制剂提供概念验证。 公共卫生相关性： 根据体重指数(BMI)30公斤/平方米的定义，超过4400万美国人患有肥胖症。肥胖是退伍军人在退伍军人医疗中心接受治疗的一个重大健康问题。2000年对近200万退伍军人的综合分析表明，~68%的退伍军人超重，~37%的退伍军人肥胖。目前治疗和预防肥胖症的策略主要集中在通过抑制食欲和行为矫正来减少能量消耗。最近的注意力集中在一种有吸引力的替代方法上，即通过增强成年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自体趋化蛋白负责产生具有生物活性的LPA，可能调节棕色脂肪组织的功能状态。本研究的目的是确定自体趋化蛋白/LPA信号通路在调节脂肪组织和饮食诱导的肥胖中的作用。我们的结果可能会为预防和治疗人类肥胖提供创新的目标。