Lipid Metabolism in Fat Cells

脂肪细胞中的脂质代谢

• 批准号: 7333302
• 负责人: WEN GUO
• 金额: $ 28.19万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7333302
• 关键词: 5' -AMP-activated protein kinase; Address; Adipocytes; Adipose tissue; Agonist; Antioxidants; Attenuated; Biochemical; Body fat; Caprylates; Cellular biology; Chemicals; Complement; Complex; Condition; Data; Development; Down-Regulation; Elevation; Event; Fasting; Fatty acid glycerol esters; Fostering; Future; Gene Expression; Gene Targeting; Generations; Genes; Grant; Health; Human; In Vitro; Lead; Left; Light; Link; Lipids; Literature; Malonyl Coenzyme A; Mediator of activation protein; Medium chain fatty acid; Messenger RNA; Metabolic; Metabolic Control; Microarray Analysis; Mitochondria; Mitogen-Activated Protein Kinases; Modeling; Molecular Biology; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutrient; Obesity; PPAR gamma; Phosphorylation; Phosphotransferases; Post-Transcriptional Regulation; Process; Proteins; Regulation; Research Personnel; Resistance; Rodent; Rodent Model; Role; Rosa; Serine; Signal Pathway; Signal Transduction; Signaling Molecule; Stress; Testing; Transcriptional Activation; Transcriptional Regulation; Triglycerides; Up-Regulation; Work; base; caprylate; deprivation; design; energy balance; feeding; gene repression; in vivo; insight; lipid biosynthesis; lipid metabolism; mutant; novel strategies; oxidation; prevent; programs; response; stressor; transcription factor

Obesity is a major health problem that predisposes to type 2 diabetes and other serious conditions. A more complete understanding of how fat synthesis is regulated in adipocytes is critical to guide rational development of new approaches for treating obesity and its complications. In the last grant period, we demonstrated that medium-chain fatty acids (octanoate) stimulate beta-oxidation and inhibit triglyceride synthesis in adipocytes, mimicking some of the metabolic effects of fasting. Analogous anti-lipogenic effects have been found in adipocytes treated with TNFalpha. We demonstrated that the three stressors,fasting in vivo, octanoate, and TNFalpha in vitro, induce many of the same cellular responses. These include increased generation of reactive oxidative species (ROS), activation of MAP-kinases (MARK) and AMP- activated protein kinase (AMPK), and decreased expression of the nuclear transcription factor PPARgamma and associated lipogenic genes. In light of these findings, we plan to use these three stressorsto manipulate lipogenesis in adipocytes to dissect mechanisms of regulation. We hypothesize that critical signals (ROS or ROS-independent) are generatedas a result of increased beta-oxidation.These signaling molecules activate stress-responsive kinases, which inactivate PPARgamma,attenuating expression of genes necessary for fat synthesis. To test this hypothesis, we propose the following specific aims: (1) to determine whether ROS is crucial for regulation of lipogenesis; (2) to test if changes in beta-oxidation generate critical signals that cause inactivation of PPARgamma; and (3) to determine if PPARgamma is the point at which signals converge that control stress-induced anti-lipogenic effects, what is the mechanism of PPARgamma inactivation, and which metabolic genes are most sensitive to the stress manipulation. Each aim will be addressed with comprehensive and integratedapplication of cell biology and molecular biology in combination with metabolic and biochemical approaches, using culture murine and human adipocytes as well as rodent models. Together, these studies will provide new insights into the stress-induced regulation of lipogenesis in adipocytes, a potentially important avenue for modulating energy balance.

肥胖是一个主要的健康问题，容易引发 2 型糖尿病和其他严重疾病。一个更多 完整了解脂肪细胞中脂肪合成的调节机制对于指导合理的脂肪合成至关重要。 开发治疗肥胖及其并发症的新方法。在上一个资助期内，我们 证明中链脂肪酸（辛酸）刺激β-氧化并抑制甘油三酯 脂肪细胞中的合成，模仿禁食的一些代谢效应。类似的抗脂肪生成作用 已在用 TNFα 处理的脂肪细胞中发现。我们证明了三种压力源，禁食 体内辛酸和体外TNFα可诱导许多相同的细胞反应。这些包括 活性氧化物质 (ROS) 的产生增加，MAP 激酶 (MARK) 和 AMP- 的激活 激活蛋白激酶 (AMPK)，并减少核转录因子 PPARgamma 的表达 和相关的脂肪生成基因。根据这些发现，我们计划使用这三个压力源来操纵 脂肪细胞中的脂肪生成来剖析调节机制。我们假设关键信号（ROS 或 ROS 独立的）是由于 β-氧化增加而产生的。这些信号分子激活 应激反应激酶，使 PPARgamma 失活，减弱脂肪必需基因的表达 合成。为了检验这一假设，我们提出以下具体目标：（1）确定ROS是否是 对于调节脂肪生成至关重要； (2) 测试β-氧化的变化是否产生关键信号 导致 PPARgamma 失活； (3) 确定 PPARgamma 是否是信号发出的点 控制应激诱导的抗脂肪生成作用的汇聚点，PPARgamma 的机制是什么 失活，以及哪些代谢基因对应激操作最敏感。每个目标都将是 细胞生物学和分子生物学的综合综合应用 结合代谢和生化方法，使用培养的小鼠和人类脂肪细胞作为 以及啮齿动物模型。总之，这些研究将为压力诱导的调节提供新的见解。 脂肪细胞中的脂肪生成，是调节能量平衡的潜在重要途径。