FATTY ACID ALPHA OXIDATION IN ADIPOCYTES

脂肪细胞中的脂肪酸α氧化

• 批准号: 7574285
• 负责人: Xiong Su
• 金额: $ 19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7574285
• 关键词: 3T3-L1 Cells; ATP Synthesis Pathway; Acetyl Coenzyme A; Address; Adenoviruses; Adipocytes; Adipose tissue; Affect; Age; Back; Body fat; Burn injury; CD36 gene; Carbon; Cardiovascular Diseases; Catabolism; Cells; Chemicals; Complications of Diabetes Mellitus; Coupled; Data; Dependence; Developed Countries; Diabetes Mellitus; Diet; Energy Metabolism; Epidemic; Etiology; Fatty Acids; Fatty acid glycerol esters; Figs - dietary; Functional disorder; Futile Cycling; Genes; Glucose Transporter; Heating; Homeostasis; Insulin; Knockout Mice; Knowledge; Lead; Length; Leptin; Lipids; Mediating; Membrane; Metabolic; Metabolic Diseases; Mitochondria; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obese Mice; Obesity; Pathway interactions; Peripheral; Physiological; Play; Population; Process; Production; Property; Proteins; Rattus; Regulation; Resistance; Role; Saturated Fatty Acids; Signal Transduction; Spectrometry, Mass, Electrospray Ionization; Stearoyl-CoA Desaturase; Tissues; Triglycerides; Unsaturated Fatty Acids; Very Long Chain Fatty Acid; Work; adenylate kinase; adipokines; branched chain fatty acid; chemical property; db/db mouse; fatty acid metabolism; fatty acid oxidation; glucose transport; in vivo; indexing; insight; insulin sensitivity; insulin signaling; ketogenesis; knock-down; lipid metabolism; lipid transport; long chain fatty acid; novel; novel strategies; novel therapeutics; oxidation; peroxisome; prevent; public health relevance; response; trafficking

DESCRIPTION (provided by applicant): Adipose tissue plays a critical role in storing triglycerides and also secretes adipokines mediating lipid metabolism and insulin sensitivity in peripheral tissues. Understanding the mechanisms underlying control of chemical energy storage and utilization in adipocytes is central to containing the epidemic of obesity. While mitochondrial fatty acid oxidation is tightly coupled to ATP synthesis, peroxisomal fatty acid oxidation generates heat at the expense of chemical energy and may work as an uncoupling process that limits adipocyte expansion. In peroxisomes, FA can undergo ¿ as well as a oxidation. It is known that peroxisomal a oxidation is important for catabolism of branched chain FA and also for very long chain FA (VLCFA). Recent data also support the role of a oxidation pathway in LCFA oxidation but its contribution to catabolism of these FA in vivo and its overall role in adipocyte energy homeostasis remain largely unknown. Using electrospray ionization mass spectrometry (ESI/MS), we demonstrated an increased activity of peroxisomal FA a oxidation during differentiation of 3T3-L1 cells to adipocytes, which was reflected in accumulation of odd numbered shorter acyl moieties in major lipid species. The physiological significance of such a change in lipid composition is unexplored. We hypothesize that LCFA a oxidation affects lipid accumulation through futile cycling of the FA generated by lipogeneis and that it may mediate some of the action of leptin to increase FA catabolism in adipose tissue. Another effect of active a oxidation is to increase the proportion of lipids with shorter acyl chains. Since intracellular lipid trafficking is highly dependent on the chemical property of acyl chains, we also hypothesize that LCFA a oxidation may alter trafficking of glucose transporters in response to insulin signaling. Accordingly, Aim 1 seeks to define how LCFA a oxidation is regulated in adipocytes, its substrate selectivity and dependence on SCD-1 activity. Aim 2 will study the role of LCFA a oxidation in energy homeostasis and lipid accumulation by examining cultured adipocytes where a oxidation is manipulated by chemical inhibition, gene knock down and protein over-expression. Obese mice (ob/ob and db/db), mice resistant to diet induced obesity (CD36 null and SCD-1 null) and mice of different ages are employed to confirm its function in vivo. Aim 3 will investigate LCFA a oxidation-mediated trafficking of glucose transporter in response to insulin signaling in adipocytes. Insights gained from this work will enhance our knowledge related to the role of a previously underappreciated pathway in the regulation of adipocyte lipid and energy metabolism. The work may lead to new concepts related to the etiology of adiposity and guide novel strategies aiming to prevent obesity and its associated complications, diabetes, and cardiovascular disease. PUBLIC HEALTH RELEVANCE: Obesity and diabetes are affecting an alarming proportion of the population in industrialized nations. Our study will gain significant insights into a novel pathway of fatty acid metabolism and the etiology of obesity and diabetes and will aid in the discovery of novel targets for treatment of these metabolic diseases.

描述（由适用提供）：脂肪组织在储存甘油三酸酯中起着至关重要的作用，并分泌脂肪因子介导脂质代谢和外周组织中胰岛素敏感性。了解脂肪细胞中化学能量储存和利用的基础机制对于包含肥胖症的流行是至关重要的。线粒体脂肪酸氧化与ATP合成紧密耦合，而过氧化物体脂肪酸氧化以牺牲化学能的代价产生热量，并且可能是限制脂肪细胞膨胀的解偶联过程。在过氧化物组中，FA可以进行氧化和氧化。众所周知，过氧化物体A氧化对于分支链FA的分解代谢很重要，对于长链FA（VLCFA）也很重要。最近的数据还支持氧化途径在LCFA氧化中的作用，但其对这些FA的体内分解代谢的贡献及其在脂肪细胞能量稳态中的总体作用仍然很大。使用电喷雾电离质谱法（ESI/MS），我们证明了3T3-L1细胞与脂肪细胞分化期间过氧化物体FA A氧化的活性增加，这反映在主要脂质物种中奇数奇数短的酰基部分较短的酰基部分。这种变化脂质组成的物理意义是出乎意料的。我们假设LCFA A氧化会通过脂肪生成产生的FA循环影响脂质的积累，并且它可能介导瘦素的某些作用以增加脂肪组织中的FA分解代谢。主动氧化的另一个作用是增加脂质较短的酰基链的比例。由于细胞内脂质运输高度依赖于酰基链的化学性质，因此我们还假设 LCFA氧化可能会因胰岛素信号传导而改变葡萄糖转运蛋白的运输。根据，AIM 1试图定义LCFA A氧化如何在脂肪细胞中调节其底物选择性和对SCD-1活性的依赖性。 AIM 2将通过检查培养的脂肪细胞来研究LCFA A氧化在能量稳态和脂质积累中的作用，在该培养的脂肪细胞中，通过化学抑制，基因敲低和蛋白质过表达来操纵氧化。肥胖小鼠（OB/OB和DB/DB），对饮食诱导的肥胖症（CD36 NULL和SCD-1 NULL）的抗性小鼠，并采用了不同年龄的小鼠来确认其在体内的功能。 AIM 3将研究LCFA A氧化介导的葡萄糖转运蛋白的运输，响应脂肪细胞中的胰岛素信号传导。从这项工作中获得的见解将增强我们与以前未被充分认识的途径在调节脂肪细胞脂质和能量代谢中的作用相关的知识。这项工作可能导致与肥胖病学有关的新概念，并指导新型策略旨在预防肥胖症及其相关并发症，糖尿病和心血管疾病。公共卫生相关性：肥胖和糖尿病正在影响工业化国家中人口的惊人比例。我们的研究将获得对脂肪酸代谢的新途径以及肥胖和糖尿病病因的新途径。并将有助于发现这些新型代谢疾病的新靶标。