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

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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.