FATTY ACID ALPHA OXIDATION IN ADIPOCYTES

脂肪细胞中的脂肪酸α氧化

• 批准号: 7861228
• 负责人: Xiong Su
• 金额: $ 2.36万
• 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 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7861228
• 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（由申请人提供）：脂肪组织在储存甘油三酯方面发挥着关键作用，并且还分泌介导外周组织中脂质代谢和胰岛素敏感性的脂肪因子，了解脂肪细胞中化学能储存和利用的控制机制对于遏制脂肪细胞的流行至关重要。虽然线粒体脂肪酸氧化与 ATP 合成紧密结合，但过氧化物酶体脂肪酸氧化会以化学能为代价产生热量，并且可能作为解偶联过程发挥作用。在过氧化物酶体中，FA 可以限制脂肪细胞的扩张。众所周知，过氧化物酶体 a 氧化对于支链 FA 和超长链 FA (VLCFA) 的分解代谢很重要，最近的数据也支持氧化途径在 LCFA 氧化中的作用，但它对分解代谢的贡献。使用电喷雾电离质谱法，这些 FA 在体内的作用及其在脂肪细胞能量稳态中的总体作用仍然很大程度上未知。 (ESI/MS)，我们证明了 3T3-L1 细胞分化为脂肪细胞期间过氧化物酶体 FA 氧化活性增加，这反映在主要脂质种类中奇数较短酰基部分的积累上。这种变化的生理意义。我们发现，LCFA 氧化通过脂肪生成产生的 FA 的无效循环来影响脂质积累，并且它可能介导 LCFA 的一些作用。瘦素增加脂肪组织中 FA 分解代谢的另一个作用是增加具有较短酰基链的脂质的比例，因为细胞内脂质运输高度依赖于酰基链的化学性质，我们也得出了这一结论。 LCFA a 氧化可能会改变葡萄糖转运蛋白响应胰岛素信号的运输。因此，目标 1 旨在确定 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，目标 2 将研究 LCFA a 氧化的作用。通过检查培养的脂肪细胞来观察能量稳态和脂质积累中的氧化，其中氧化是通过化学抑制、基因敲低和蛋白质过度表达来操纵的。肥胖小鼠（ob/ob 和 db/db）、抗饮食诱导肥胖的小鼠（CD36 null 和 SCD-1 null）和不同年龄的小鼠被用来确认其体内功能，目的 3 将研究 LCFA a 氧化介导的功能。从这项工作中获得的见解将增强我们对脂肪细胞脂质和能量代谢调节中先前未被充分认识的途径的作用的认识。与肥胖病因学相关的新概念，并指导旨在预防肥胖及其相关并发症、糖尿病和心血管疾病的新策略。 公共卫生相关性：肥胖和糖尿病正在影响工业化国家中令人震惊的人口比例。对脂肪酸代谢的新途径以及肥胖和糖尿病的病因学获得重要见解，并将有助于发现治疗这些代谢疾病的新靶点。