METABOLIC SIGNAL TRANSDUCTION IN ADIPOCYTES

描述：控制脂肪细胞质量和脂肪细胞大小可能是信号的结果 在大脑或其他组织中产生，但最终是细胞事件 以一种受监管的方式转化为燃料分配的挥发， 可能是由于特定的酶和代谢物浓度 现在时。支持这一概念的证据来自观察 尽管可以随意获取食物，但大多数哺乳动物保持着恒定的 体重和恒定脂肪质量。拟议研究的重点是 了解游离脂肪酸(FFA)在 利用(产生能量或热量)和沉积(如甘油三酯) 脂肪细胞和可能的关键酶的变化的影响 调节脂肪堆积的分配。存储和存储之间的分区 处置受到酶水平的监管，每分钟一次。 时间尺度，而酶水平受到转录调节，在一个 更长的时间尺度。特别是，酰基辅酶A合成酶对于 生成长链酰基辅酶A(LC-CoA)，氧化和还原的前体 复合脂形成，而肉碱棕榈酰转移酶-1(CPT-1)， 乙酰辅酶A羧基酶和解偶联蛋白(UCP)控制着 代谢活性形式的游离脂肪酸，LC-CoA。据推测，细胞与 CPT-1或UCP活性低的β-氧化率较低，高水平的 丙二酰辅酶A和LC-辅酶A，以及比细胞更大的积累脂质的能力 具有较高的CPT-1或UCP活性。此外，改变酶的表达，将会 改变燃料分配。初步数据记录了不同水平的 LC-CoA、CPT-1敏感性和异构体分布以及脂质能力 大鼠和人体内的蓄积和FFA摄取(即使在单细胞水平上) 来自不同地区的前脂肪细胞，在培养中已分化。 具体目标将使用3T3-L1解决以下问题 前脂肪细胞和大鼠脂肪细胞。1.β-氧化如何随 脂肪细胞的营养和转录调控？2.哪些酶 调节FFA的细胞内分配？3.LC和丙二酰辅酶A是否发挥作用 FFA分配的代谢控制？4.FFA或LC-CoA是否参与调节 线粒体的能量效率还是UCP的活性？

DESCRIPTION: Control of fat cell mass and fat cell size may result from signals generated in the brain or from other tissues but ultimately cellular events transpire that are translated into partitioning of fuels in a regulated manner, presumably due to the particular enzyme and metabolite concentrations that are present. Evidence in support of this concept is derived from the observation that, despite ad libitum access to food, most mammals maintain a constant weight and constant fat mass. The focus of the proposed studies is to understand regulation of partitioning of free fatty acids (FFA) between utilization (to produce energy or heat) and deposition (as triglyceride) in adipocytes and the impact of alterations in the putative key enzymes that regulate partitioning on fat accumulation. Partitioning between storage and disposal is subject to regulation at the enzymatic level on a minute-to-minute time scale, while enzyme levels are subject to transcriptional regulation, on a longer time scale. In particular, acyl CoA synthase is essential for the generation of long chain acyl CoA (LC-CoA), the precursor to both oxidation and complex lipid formation, while carnitine palmitoyl transferase-1 (CPT-1), acetyl CoA carboxylase and uncoupling proteins (UCPs) control the fate of the metabolically active form of FFA, LC-CoA. It is hypothesized that cells with low CPT-1 or UCP activity have lower rates of beta-oxidation, higher levels of malonyl CoA and LC-CoA, and a greater capacity to accumulate lipid than cells with high CPT-1 or UCP activity. Further, that altering enzyme expression, will change fuel partitioning. Preliminary data document differences in levels of LC-CoA, CPT-1 sensitivity and isoform distribution, and capacities for lipid accumulation and FFA uptake (even at the single cell level) in rat and human preadipocytes from different regions that have been differentiated in culture. The Specific Aims will address the following questions using 3T3-L1 preadipocytes and rat adipocytes. 1. How does beta-oxidation vary with nutritional and transcriptional manipulations in fat cells? 2. Which enzymes regulate intracellular partitioning of FFA? 3. Do LC- and malonyl-CoA exert metabolic control over FFA partitioning? 4. Do FFA or LC-CoA modulate mitochondrial energy efficiency or the activity of UCP?