Lipid Metabolism in Fat Cells

肥胖是一个主要的健康问题，容易导致2型糖尿病和其他严重的疾病。A更多 完全了解脂肪细胞中脂肪合成是如何调节的，这对于指导理性 开发治疗肥胖症及其并发症的新方法。在上一次授权期内，我们 证明中链脂肪酸(辛酸)促进β-氧化和抑制甘油三酯 脂肪细胞的合成，模仿禁食的一些新陈代谢效应。类似的降脂作用 在用肿瘤坏死因子α处理的脂肪细胞中发现了这种情况。我们证明了这三个压力源，禁食 在体外，活体、辛酸和肿瘤坏死因子α可引起许多相同的细胞反应。这些措施包括 活性氧化物种(ROS)的生成增加，MAP-Kase(MARK)和AMP- 活化的蛋白激酶(AMPK)和核转录因子PPARγ的表达降低 以及相关的生脂基因。根据这些发现，我们计划利用这三种压力来操纵 脂肪细胞中的脂肪生成，以剖析调节机制。我们假设关键信号(ROS或 不依赖于ROS)是由于β-氧化增加而产生的。这些信号分子激活 应激反应蛋白激酶，可使PPARγ失活，减弱脂肪必需基因的表达 综合。为了验证这一假设，我们提出了以下具体目标：(1)确定ROS是否 对脂肪生成的调节至关重要；(2)测试β-氧化的变化是否产生关键信号 导致PPARGamma失活；以及(3)确定PPARGamma是否是信号点 汇聚控制应激诱导的抗脂作用，PPARGamma的作用机制是什么 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 阐述了细胞生物学和分子生物学在医学中的综合应用 结合代谢和生化方法，以培养的小鼠和人脂肪细胞为 还有啮齿动物模型。总之，这些研究将为压力诱导的调节机制提供新的见解。 脂肪细胞的脂肪生成，一个潜在的调节能量平衡的重要途径。

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.