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: 10426085
• 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/10426085
• 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; 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 of activation protein; 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; activity marker; amino acid metabolism; blood glucose regulation; diet-induced obesity; experimental study; glucose metabolism; glucose uptake; improved; inflammatory marker; insulin sensitivity; insulin sensitizing drugs; 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.

血栓素 A2 (TXA2) 是一种源自花生四烯酸的促炎脂质介质，可发挥 它通过血栓素-前列腺素受体（TP-R）产生生物学效应。然而，目前 TP-R 是否可以调节代谢途径尚不清楚。虽然脂肪细胞主要是 参与储存过量甘油三酯，新出现的证据表明它们具有 在氨基酸 (AA) 代谢中发挥重要作用，特别是支链 AA；值得注意的是，升高 支链氨基酸的血浆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仍不清楚。初步的 数据提供证据表明，缺乏 TP-R 的小鼠（TP-R-/- 小鼠）在暴露于高浓度环境时会变瘦。 热量饮食。此外，TP-R-/- AT 中组氨酸分解代谢标记物显着增加 老鼠被注意到。此外，这些小鼠表现出 AT 炎症的减少和 高脂肪饮食下的胰岛素敏感性和葡萄糖稳态。因此，总体假设是 TP-R 在介导肥胖相关炎症和胰岛素方面发挥重要作用 通过改变脂肪组织中的组氨酸和/或葡萄糖代谢来抵抗。临床， 将采用生物化学和分子方法来确定 TP-R 作为药物的潜力 肥胖相关胰岛素抵抗的治疗靶点并研究其机制 TP-R 阻断可改善胰岛素抵抗、炎症以及组氨酸和葡萄糖 AT 中的代谢。在具体目标 1 中，我们将进行皮下和内脏 AT 的研究 从瘦/超重胰岛素敏感和肥胖胰岛素抵抗受试者中收集 PBMC。 我们将比较瘦/超重胰岛素在 AT 和 PBMC 中的 TP-R 表达 敏感和肥胖胰岛素抵抗受试者并确定 TP-R 作为目标的潜力 用于治疗人类肥胖相关的胰岛素抵抗。另外，详细 机制研究将在培养的 AT 外植体、原代脂肪细胞和 人脂肪细胞系以确定 TP-R 促进胰岛素的机​​制 反抗。在具体目标 2 中，我们将内脏和皮下 AT TP-R 关联起来 与炎症标志物的表达。此外，我们将通过以下方式确定机制： 其中 TP-R 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 与组氨酸相关联 AT 中的转运蛋白，特别是 Slc15a4。此外，我们还将开展文化研究 外植体和细胞以确定 TP-R 在调节组氨酸和/或 葡萄糖代谢。这些发现将有助于揭示 TP-R 在代谢中的作用 控制和开发新的治疗策略来管理肥胖和肥胖类型的高血糖 2 糖尿病。