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未能充分扩大脂肪组织块有关。最近的研究表明，胰岛素抵抗患者在脂肪形成方面存在缺陷，而导致这一缺陷的机制仍然知之甚少。在这个建议中，我们将研究脂质信号在这种脂肪性缺陷产生中的潜在作用。我们之前的工作旨在了解以脂肪缺失为特征的胰岛素抵抗的极端表型：继发于AGPAT2突变的先天性全身性脂肪营养不良。我们确定脂肪形成的缺陷是继发于PI3K/Akt通路和脂肪形成的主要调节因子PPAR¿的错误激活。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也调节脂肪形成。因此，利用TAG合成途径将是前脂肪细胞检测脂肪酸通量增加并产生刺激脂肪形成的中间体的有效途径。事实上，具有调节脂肪形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，个体产生促脂肪信号（溶血磷脂酸vs环磷脂酸）的内在能力增强，可以防止肥胖引起的胰岛素抵抗。为了验证这一假设，我们计划首先确定不同的影响

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. PUBLIC HEALTH RELEVANCE: Patients predisposed to the development of type 2 diabetes and heart disease have a more limited capacity of storing fatty acids which are then 'spill over' other tissues. This causes the toxic effects typically seen in these conditions. This proposal will examine the cause underlying the defect in storage capacity of adipose tissue.