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

TP-R：人类肥胖相关胰岛素抵抗的新型介质

• 批准号: 10709488
• 负责人: Cyrus V Desouza
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709488
• 关键词: Abdomen; Adipocytes; Adipose tissue; Affect; Amidohydrolases; Amino Acids; Anti-Inflammatory Agents; Arachidonic Acids; Binding; Biochemical; Biological; Body Weight; Branched-Chain Amino Acids; Case/Control Studies; Catabolism; Cell Line; Cells; Clinical; Clinical Investigator; Clinical Research; Collaborations; Collecting Cell; Correlation Studies; Data; Development; Diet; Enzymes; Essential Amino Acids; Exposure to; Fatty Acids; Future; General Population; Genes; Glucose; Hemostatic function; High Fat Diet; Histidine; Histidine Ammonia-Lyase; Histidine Metabolism Pathway; Human; Hyperglycemia; IL8 gene; Individual; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Link; Measures; Mediating; Mediator; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolism; Mission; Molecular; Morbid Obesity; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Operative Surgical Procedures; Overweight; PTEN gene; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Plasma; Play; Process; Prostaglandins; Proteins; Proto-Oncogene Proteins c-akt; Receptor Activation; Receptor Gene; Regulation; Research; Risk; Risk Factors; Role; Scientist; Signal Transduction; Stimulus; Supplementation; Therapeutic; Thinness; Thromboxane A2; Thromboxanes; Triglycerides; Veterans; Visceral; amino acid metabolism; blood glucose regulation; comparison control; diet-induced obesity; experimental study; glucose metabolism; glucose uptake; improved; inflammatory marker; insulin sensitivity; insulin signaling; lipid mediator; mRNA Expression; member; mouse model; novel; novel therapeutic intervention; novel therapeutics; obese patients; obese person; obesity management; peripheral blood; preclinical study; receptor; receptor expression; small molecule inhibitor; subcutaneous; targeted treatment; therapeutic target; translational study; uptake; vasoconstriction

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.

血栓烷A2（TXA2），一种源自花生四烯酸的促炎性脂质介质，施加 它通过血栓烷螺旋体受体（TP-R）的生物效应。但是，目前是 未知TP-R是否可以调节代谢途径。虽然脂肪细胞主要是 参与过多甘油三酸酯的储存，新出现的证据表明他们有 在氨基酸（AA）代谢中的重要作用，特别是分支链AA；值得注意的是，高架 分支链AAS的血浆水平与胰岛素抵抗密切相关。但是， 脂肪组织（AT）在其他基本AA的代谢中的作用尚不清楚。初步 数据提供了证据表明缺乏TP-R（TP-R - / - 小鼠）的小鼠在暴露于高的小鼠 热量饮食。此外，在TP-R - / - AT中，组氨酸分解代谢标记的明显增加 注意到老鼠。此外，这些小鼠在炎症和改善时显示出减少 高脂饮食上的胰岛素敏感性和葡萄糖稳态。因此，总体假设是 TP-R在介导与肥胖相关的炎症和胰岛素方面起着重要作用 通过改变其脂肪组织中其和/或葡萄糖代谢的耐药性。临床， 将采用生化和分子方法来确定TP-R作为A的潜力 与肥胖相关胰岛素耐药性中的治疗靶标，并通过 TP-R阻滞可改善胰岛素抵抗，炎症以及组氨酸和葡萄糖 AT中的代谢。在特定目标1中，我们将在和内脏进行研究和内脏。 从瘦/超重胰岛素敏感和肥胖胰岛素耐药的受试者中收集的PBMC。 我们将在瘦/超重胰岛素之间比较AT和PBMC中的TP-R表达 敏感和肥胖的胰岛素耐药受试者，并确定TP-R作为靶标的潜力 用于针对人类肥胖连接胰岛素耐药性的治疗。另外，详细 机械研究将在外植体，主要脂肪细胞和 人脂肪细胞细胞线以确定TP-R促进胰岛素的机​​制 反抗。在特定的目标2中，我们将在TP-R处将内脏和皮下相关联 带有炎症标记的表达。此外，我们将通过 TP-R促进了在外植体，脂肪细胞线和PBMC中的炎症反应。 在特定的目标3中，我们将在TP-R处将内脏和皮下与组氨酸相关联 AT中的转运蛋白，特别是SLC15A4。此外，我们将在培养中进行研究 外植体和细胞确定TP-R在调节组氨酸和/或调制组氨酸和/或的作用和机制 葡萄糖代谢。这些发现将与发现TP-R在代谢中的作用有关 控制和制定新的治疗策略，以管理肥胖和类型中的高血糖 2个糖尿病。