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: 8391631
• 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/8391631
• 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.

描述（由申请人提供）： 项目摘要/摘要 肥胖和与肥胖相关的心血管并发症是美国日益严重的健康负担。对 2000 年在 VA 医疗中心接受护理的近 200 万退伍军人进行的分析表明，约 68% 的人超重，约 37% 的人肥胖。尽管进行了广泛的研究，但防止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个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，这样的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，以生理相关水平存在于血浆和其他生物液体中，在人类健康和疾病中发挥作用。分泌型溶血磷脂酶 D 自分泌运动因子 (autotaxin/lysoLPD) 负责产生细胞外的具有生物活性的 LPA，而 LPA 又通过脂质磷酸酶 (LPP) 的酶促去磷酸化而失活。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会降低棕色脂肪细胞分化标记物和 LPP3（Wnt 的内源性调节因子）的表达；而新型自分泌运动因子/lysoPLD 抑制剂可显着促进棕色脂肪细胞分化。在小鼠中，自分泌运动因子的过度表达会降低 UCP1 的表达并促进饮食诱导的肥胖。因此，我们提出了一个中心假设：自分泌运动因子和 LPP3 调节的信号通路有助于饮食诱导的生热作用并调节饮食诱导的肥胖的发展。我们将使用最先进的遗传和药理学方法在三个特定目标上测试我们的中心假设。在目标一中，我们将确定自分泌运动因子/lysoPLD 在动物模型中调节棕色脂肪组织和饮食诱导的肥胖中的作用。在目标二中，我们将建立 LPA 和自分泌运动因子发挥作用的分子机制。在目标三中，我们确定了 LPP3 在脂肪组织发育和功能以及饮食引起的肥胖中的作用。这笔赠款的目的是提供一种工具来解决溶血脂信号传导领域尚未解决的主要问题，即自分泌运动因子/lysoPLD、LPA 和 LPP3 在肥胖调节中的作用。这些结果将具有重要意义，因为它们有望提供创新靶标，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。