Role of lipid intermediates in the limited human adipose tissue expandability ass

描述（由申请人提供）：2型糖尿病及其相关心血管并发症的发生与未能充分扩张脂肪组织质量有关。最近的研究表明，胰岛素抵抗患者存在脂肪生成缺陷，导致这一缺陷的机制仍然知之甚少。在这个建议中，我们将调查的潜在作用，脂质信号在产生这种脂肪形成缺陷。我们以前的工作是针对了解一种极端的胰岛素抵抗表型，其特征是缺乏脂肪：继发于AGPAT 2突变的先天性全身性脂肪营养不良。我们确定，脂肪形成的缺陷是继发于PI 3 K/Akt通路和脂肪形成的主要调节因子PPAR？的错误激活。AGPAT 2是甘油三酯（TAG）合成途径的一部分，该途径中的另一种酶GPAT 3也调节脂肪生成。因此，TAG合成途径的利用将是前脂肪细胞检测增加的脂肪酸通量并产生将刺激脂肪生成的中间体的有效方式。事实上，具有调节脂肪形成能力的脂质中间体可以通过该途径产生（即，作为PPAR？拮抗剂的环磷脂酸）。我们假设，在脂肪酸供应增加的情况下，具有产生促脂肪形成信号（溶血磷脂酸与环状磷脂酸）的增强的内在能力的个体受到保护，免受肥胖诱导的胰岛素抵抗。为了验证这一假设，我们计划首先确定不同的 TAG合成途径中的酶在产生能够调节脂肪形成的生物活性脂质中的作用。在第二个具体目标中，我们将确定TAG合成酶对与暴露于高浓度营养素相关的脂肪形成障碍的影响。在第三个具体目标中，我们将确定与肥胖胰岛素敏感个体相比，来自肥胖胰岛素抵抗个体的前脂肪细胞是否在产生来自TAG合成途径的促脂肪形成脂质中间体方面存在缺陷。为了实现这一点，我们将比较来自TAG途径的脂质中间体的稳态水平和利用13 C标记的脂肪酸通过TAG合成途径的标记速率。在这些研究完成后，我们将确定肥胖胰岛素抵抗个体中存在的错误脂质信号。

DESCRIPTION (provided by applicant): The development of type 2 diabetes and its associated cardiovascular complications has been linked to a failure to adequately expand adipose tissue mass. Recent studies have demonstrated that patients with insulin resistance have a defect in adipogenesis and the mechanisms leading to this are still poorly understood. In this proposal we will investigate the potential role of lipid signals in the generation of this adipogenic defect. Our previous work was targeted towards the understanding of an extreme phenotype of insulin resistance characterized by the absence of fat: congenital generalized lipodystrophy secondary to the AGPAT2 mutation. We determined that the defect in adipogenesis was secondary to a faulty activation of the PI3K/Akt pathway and the master regulator of adipogenesis, PPAR¿. AGPAT2 is part of the triglyceride (TAG) synthesis pathway, and another enzyme in this pathway, GPAT3, also regulates adipogenesis. Thus the utilization of the TAG synthesis pathway would be an efficient way for preadipocytes to detect increased flux of fatty acids and produce intermediates that would stimulate adipogenesis. Indeed lipid intermediates with the capacity to regulate adipogenesis can be generated by this pathway (i.e. cyclic phosphatidic acid as a PPAR¿ antagonist). We hypothesize that individuals with an enhanced intrinsic capacity for generating pro-adipogenic signals (lysophosphatidic acid vs. cyclic phosphatidic acid) in the face of increased fatty acid supply are protected from obesity-induced insulin resistance. To test this hypothesis we plan to first determine effects of different enzymes from the TAG synthesis pathway in the generation of bioactive lipids capable of regulating adipogenesis. In the second specific aim we will determine effects of TAG synthesis enzymes on the adipogenic impairment associated with exposure to a high concentration of nutrients. In the third specific aim we will determine if preadipocytes from obese insulin-resistan individuals have a defect in the generation of pro-adipogenic lipid intermediates derived from the TAG synthesis pathway when compared to obese insulin sensitive individuals. To accomplish this we will compare steady state levels of lipid intermediates from the TAG pathway and the rate of labeling through the TAG synthesis pathway utilizing 13C labeled fatty acids. At the completion of these studies we will have defined the faulty lipid signal present in obese insulin-resistant individuals.