TP-R: a novel mediator of obesity-linked insulin resistance in humans

血栓素A2(TXA2)，一种源于花生四烯酸的促炎脂质介质， 其生物学效应通过血栓烷-前列腺素受体(TP-R)实现。不过，目前 尚不清楚TP-R是否可以调节代谢途径。虽然脂肪细胞主要是 参与了过量甘油三酯的储存，新出现的证据表明，它们有一个 在氨基酸(AA)代谢中的重要作用，特别是支链氨基酸；值得注意的是， 血浆支链氨基酸水平与胰岛素抵抗密切相关。然而， 脂肪组织(AT)在其他必需氨基酸代谢中的作用尚不清楚。预赛 数据提供证据表明，缺乏TP-R的小鼠(TP-R-/-小鼠)在暴露于高强度的 卡路里饮食。此外，TP-R-/-AT的组氨酸分解代谢标志物显著增加 老鼠被记录下来。此外，这些小鼠显示出AT炎症的减少和 高脂饮食中的胰岛素敏感性和血糖稳态。因此，总体假设是 TP-R在介导肥胖相关炎症和胰岛素中起重要作用 抗性通过改变脂肪组织中的His和/或葡萄糖代谢来实现。临床上， 生化和分子方法将被用来确定TP-R作为一种 肥胖相关胰岛素抵抗的治疗靶点及机制探讨 哪种TP-R阻滞剂可改善胰岛素抵抗、炎症、组氨酸和血糖 AT的新陈代谢。在具体目标1中，我们将进行皮下和内脏AT和 采集自瘦/超重的胰岛素敏感和肥胖的胰岛素抵抗受试者的PBMC。 我们将比较瘦胰岛素和超重胰岛素对AT和PBMC中TP-R表达的影响 敏感和肥胖的胰岛素抵抗患者，并确定TP-R作为靶点的潜力 用于治疗人类肥胖相关的胰岛素抵抗。此外，详细介绍了 机制研究将在培养的AT外植体、原代脂肪细胞和 用人脂肪细胞系研究TP-R促进胰岛素的机制 抵抗。在具体目标2中，我们将内脏和皮下在TP-R进行关联 有炎症标志物的表达。此外，我们将通过以下方式确定机制 哪种TP-R可促进AT外植体、脂肪细胞系和PBMC的炎症反应。 在具体目标3中，我们将内脏和皮下AT-TP-R与组氨酸联系起来 AT中的转运蛋白，特别是SLC15A4。此外，我们将在培养的 确定TP-R在调节组氨酸和/或组氨酸中的作用和机制 葡萄糖代谢。这些发现将有助于揭示TP-R在新陈代谢中的作用 控制和开发新的治疗策略来管理肥胖和2型糖尿病患者的高血糖 2糖尿病。

Thromboxane A2 (TXA2), a pro-inflammatory lipid mediator derived from arachidonic acid, exerts its biological effects via thromboxane-prostanoid receptor (TP-R). However, it is currently unknown whether TP-R can modulate metabolic pathways. Although the adipocytes are mainly involved in the storage of excess triglycerides, emerging evidence suggests that they have an important role in amino acid (AA) metabolism, in particular branched chain AAs; of note, elevated plasma levels of branched chain AAs is strongly associated with insulin resistance. However, the role of adipose tissue (AT) in the metabolism of other essential AAs is still unclear. The preliminary data provide evidence that mice lacking TP-R (TP-R-/- mice) grow lean when exposed to a high caloric diet. Moreover, a striking increase in markers of histidine catabolism in the AT of TP-R-/- mice was noted. Further, these mice showed a reduction in AT inflammation and improvement in insulin sensitivity and glucose homeostasis on a high fat diet. Therefore, the overall hypothesis is that TP-R plays an important role in mediating obesity-related inflammation and insulin resistance via altered His and/or glucose metabolism in adipose tissue. Clinical, biochemical, and molecular approaches will be employed to determine the potential of TP-R as a therapeutic target in obesity-related insulin resistance and investigate the mechanisms by which TP-R blockade improves insulin resistance, inflammation, and histidine and glucose metabolism in AT. In Specific Aim 1, we will conduct studies subcutaneous and visceral AT and PBMCs collected from lean/overweight insulin sensitive and obese insulin resistant subjects. We will compare TP-R expression in AT and PBMCs between lean/overweight insulin sensitive and obese insulin resistant subjects and determine the potential of TP-R as a target for therapy against obesity-linked insulin resistance in humans. In addition, detailed mechanistic studies will be conducted in cultured AT explants, primary adipocytes and human adipocyte cell-line to determine mechanisms by which TP-R promotes insulin resistance. In Specific Aim 2, we will correlate visceral and subcutaneous AT TP-R expression with markers of inflammation. In addition, we will determine mechanisms by which TP-R promotes inflammatory response in AT explants, adipocyte cell-line, and PBMCs. In Specific Aim 3, we will correlate visceral and subcutaneous AT TP-R with histidine transporters in AT, in particular Slc15a4. Furthermore, we will perform studies in cultured explants and cells to determine the role and mechanism of TP-R in modulating histidine and/or glucose metabolism. The findings will be relevant to uncover the role of TP-R in metabolic control and develop novel therapeutic strategies to manage hyperglycemia in obesity and type 2 diabetes.