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
- 来源:
- 关键词:AbdomenAdipocytesAdipose tissueAffectAmidohydrolasesAmino AcidsAnti-Inflammatory AgentsArachidonic AcidsBindingBiochemicalBiologicalBody WeightBranched-Chain Amino AcidsCase/Control StudiesCatabolismCell LineCellsClinicalClinical InvestigatorClinical ResearchCollaborationsCollecting CellCorrelation StudiesDataDevelopmentDietEnzymesEssential Amino AcidsExposure toFatty AcidsFutureGeneral PopulationGenesGlucoseHemostatic functionHigh Fat DietHistidineHistidine Ammonia-LyaseHistidine Metabolism PathwayHumanHyperglycemiaIL8 geneIndividualInflammationInflammatoryInflammatory ResponseInsulinInsulin ResistanceLinkMeasuresMediatingMediatorMetabolicMetabolic ControlMetabolic DiseasesMetabolic PathwayMetabolismMissionMolecularMorbid ObesityMusNon-Insulin-Dependent Diabetes MellitusObesityObesity associated diseaseOperative Surgical ProceduresOverweightPTEN genePathway interactionsPatientsPeripheral Blood Mononuclear CellPlasmaPlayProcessProstaglandinsProteinsProto-Oncogene Proteins c-aktReceptor ActivationReceptor GeneRegulationResearchRiskRisk FactorsRoleScientistSignal TransductionStimulusSupplementationTherapeuticThinnessThromboxane A2ThromboxanesTriglyceridesVeteransVisceralamino acid metabolismblood glucose regulationcomparison controldiet-induced obesityexperimental studyglucose metabolismglucose uptakeimprovedinflammatory markerinsulin sensitivityinsulin signalinglipid mediatormRNA Expressionmembermouse modelnovelnovel therapeutic interventionnovel therapeuticsobese patientsobese personobesity managementperipheral bloodpreclinical studyreceptorreceptor expressionsmall molecule inhibitorsubcutaneoustargeted treatmenttherapeutic targettranslational studyuptakevasoconstriction
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)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(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:
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