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展与脂肪组织肿块未能充分扩张有关。最近的研究表明，胰岛素抵抗患者在脂肪生成方面存在缺陷，导致这种缺陷的机制仍然知之甚少。在这项建议中，我们将研究脂质信号在这种成脂缺陷的发生中的潜在作用。我们之前的工作旨在了解一种以缺乏脂肪为特征的极端胰岛素抵抗表型：继发于AGPAT2突变的先天性全身性脂肪营养不良。我们确定，脂肪生成的缺陷是由于PI3K/Akt通路和脂肪生成的主要调节因子PPAR的错误激活所致。AGPAT2是甘油三酯(Tag)合成途径的一部分，该途径中的另一种酶GPAT3也调节脂肪生成。因此，利用TAG合成途径将是前脂肪细胞检测增加的脂肪酸通量并产生刺激脂肪形成的中间产物的有效途径。事实上，具有调节脂肪生成能力的脂质中间体可以通过这一途径产生(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，具有产生促脂肪信号(溶血磷脂酸与环磷脂酸)的内在能力增强的个体可以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 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。在第二个具体目标中，我们将确定TAG合成酶在与暴露于高浓度营养物质相关的成脂损害中的作用。在第三个特定目标中，我们将确定与肥胖的胰岛素敏感者相比，肥胖胰岛素抵抗者的前脂肪细胞是否在生成源于TAG合成途径的促脂肪中介物方面存在缺陷。为了做到这一点，我们将比较来自TAG途径的脂中间体的稳态水平和利用13C标记的脂肪酸通过TAG合成途径的标记率。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有缺陷的血脂信号。

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.