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（TXA 2）是一种由花生四烯酸衍生的促炎脂质介质， 其生物学效应通过血栓素-前列腺素受体（TP-R）实现。但目前 目前尚不清楚TP-R是否能调节代谢途径。虽然脂肪细胞主要是 参与多余甘油三酯的储存，新出现的证据表明，他们有一个 在氨基酸（AA）代谢中起重要作用，特别是支链AA;值得注意的是， 支链AA的血浆水平与胰岛素抗性密切相关。但 脂肪组织（AT）在其它必需氨基酸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的小鼠（TP-R-/-小鼠）在暴露于高浓度时会变瘦。 高热量饮食此外，在TP-R-/-AT中组氨酸催化剂标记物的显著增加， 老鼠注意到。此外，这些小鼠表现出AT炎症的减少和 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分泌中起重要作用， 通过改变脂肪组织中的His和/或葡萄糖代谢来抵抗。临床， 生物化学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，并通过 其中TP-R阻断改善胰岛素抵抗、炎症、组氨酸和葡萄糖 AT代谢在具体目标1中，我们将进行皮下和内脏AT研究， 从瘦/超重胰岛素敏感和肥胖胰岛素抵抗受试者收集PBMC。 我们将比较瘦/超重胰岛素组AT和PBMC中TP-R的表达， 敏感和肥胖的胰岛素抵抗受试者，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 将在培养的AT外植体、原代脂肪细胞和 人脂肪细胞系测定TP-R促进胰岛素的机制 阻力在特定目标2中，我们将内脏和皮下AT TP-R 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中的炎症反应。 在具体目标3中，我们将内脏和皮下AT TP-R与组氨酸 AT中的转运蛋白，特别是Slc 15 a4。此外，我们将在培养的 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，以管理肥胖和肥胖型高血糖症 2糖尿病.