METABOLIC SIGNAL TRANSDUCTION IN ADIPOCYTES

描述：脂肪细胞质量和脂肪细胞大小的控制可能来自信号 产生于大脑或其他组织，但最终是细胞事件 蒸发，转化为燃料的分配，在一个受管制的方式， 可能是由于特定的酶和代谢物浓度， 礼物支持这一概念的证据来自观察 尽管可以自由进食，但大多数哺乳动物 体重和恒定脂肪量。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（作为甘油三酯）， 脂肪细胞和改变的影响，在假定的关键酶， 调节脂肪积累的分配。在存储和 处置受到酶水平上每分钟的调节， 时间尺度，而酶水平受到转录调控，在一个 更长的时间尺度。具体地，酰基辅酶A合酶是必需的， 长链酰基辅酶A（LC-CoA）的产生，即氧化和 复合脂质形成，而肉毒碱棕榈酰转移酶-1（CPT-1）， 乙酰辅酶A羧化酶和解偶联蛋白（UCPs）控制着 FFA的代谢活性形式，LC-CoA。据推测，细胞与 CPT-1或UCP活性低，β-氧化速率低， 丙二酰辅酶A和LC-CoA，以及比细胞更大的积累脂质的能力 具有高CPT-1或UCP活性。此外，改变酶的表达， 改变燃料分配。初步数据文件显示， LC-CoA、CPT-1敏感性和亚型分布以及脂质代谢能力 大鼠和人体内的蓄积和FFA摄取（即使在单细胞水平） 来自不同区域的前脂肪细胞已在培养物中分化。 具体目标将使用3 T3-L1解决以下问题 前脂肪细胞和大鼠脂肪细胞。1.β-氧化作用如何随 脂肪细胞的营养和转录调控2.这些酶 调节FFA的细胞内分配？3. LC-和丙二酰辅酶A是否 代谢控制FFA分配？4. FFA或LC-CoA是否调节 线粒体能量效率或UCP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?