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

基本信息

  • 批准号:
    10709488
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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),一种源自花生四烯酸的促炎脂质介质,发挥作用

项目成果

期刊论文数量(0)
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Cyrus V Desouza其他文献

Racial differences in measures of glycemia in the Vitamin D and Type 2 Diabetes (D2d) Study: a secondary analysis of a randomized trial
维生素 D 和 2 型糖尿病 (D2d) 研究中血糖测量值的种族差异:随机试验的二次分析
  • DOI:
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    4.1
  • 作者:
    Erin S LeBlanc;A. Pittas;Jason Nelson;Ranee Chatterjee;Neda Rasouli;M. Rhee;R. Pratley;Cyrus V Desouza;Lisa M Neff;Anne M Peters;Sam Dagogo;Daniel S. Hsia
  • 通讯作者:
    Daniel S. Hsia

Cyrus V Desouza的其他文献

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{{ truncateString('Cyrus V Desouza', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
The Role of Apathy in Glycemic Control
冷漠在血糖控制中的作用
  • 批准号:
    7783850
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
The Role of Apathy in Glycemic Control
冷漠在血糖控制中的作用
  • 批准号:
    7687317
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:
The Role of Apathy in Glycemic Control
冷漠在血糖控制中的作用
  • 批准号:
    8195986
  • 财政年份:
    2009
  • 资助金额:
    --
  • 项目类别:

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