Altered Glucose and Lipid Metabolism in Obesity and CVD
肥胖和心血管疾病中葡萄糖和脂质代谢的改变
基本信息
- 批准号:7263925
- 负责人:
- 金额:$ 78.54万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-08-01 至 2009-07-31
- 项目状态:已结题
- 来源:
- 关键词:2,4-thiazolidinedioneAcute-Phase ProteinsAddressAdipocytesAdipose tissueAdultAffectAgeAgingAortaArterial Fatty StreakBile fluidBiliaryBiochemicalBioinformaticsBiological AssayBiological PreservationBlood VesselsBody WeightCanis familiarisCarbohydratesCardiacCardiovascular DiseasesCell membraneCellsCentral obesityCholesterolCholesterol HomeostasisClassificationComplementDataDefectDepthDevelopmentDiabetes MellitusDietDimensionsDiseaseDisease ProgressionDown-RegulationDyslipidemiasEmployee StrikesEpidemicFatty acid glycerol estersFemaleFinancial compensationGLUT4 geneGelGenderGene ExpressionGene ProteinsGene Transfer TechniquesGenesGeneticGenotypeGlucoseGlucose TransporterGlucose tolerance testGlycerolGonadal Steroid HormonesHematoxylin and Eosin Staining MethodHormonesHumanHyperglycemiaImaging TechniquesImpairmentIn VitroIndividualInsulinInsulin ResistanceLettersLinkLipidsLipolysisLipoproteinsLiverMagnetic Resonance ImagingMass Spectrum AnalysisMating TypesMeasurableMeasurementMediatingMessenger RNAMetabolicMetabolic syndromeMetabolismMethodsModelingModificationMolecularMusMuscleMutationNon-Insulin-Dependent Diabetes MellitusNuclearObesityObesity associated cardiovascular diseaseOilsOralOvariectomyOverweightPathogenesisPatientsPeripheralPhenotypePhysiologyPlasmaPolymerase Chain ReactionPopulationPrevalencePreventionProtein OverexpressionProteinsProteomicsQuarantineRelative (related person)ResistanceRiskRoleRoom, CleanSamplingSecondary toSerumSkeletal MuscleSterolsSudanSyndromeTG geneTechnologyTestingThiazolidinedionesTimeTransgenic OrganismsUnited StatesUnited States National Institutes of HealthVisceraladipokinescDNA Arraysdesigndiabeticfeedingglucose disposalheart imagingimprovedin vivoinsulin sensitivityinsulin sensitizing drugsinsulin toleranceknockout genelipid metabolismliver metabolismmalemetabolic abnormality assessmentmouse modelnovelnovel therapeuticspreventprogramsprotein expressionresearch studyresponsesecretory proteinsexsizeskeletal preservationsubcutaneoustherapeutic target
项目摘要
DESCRIPTION (provided by applicant):
Obesity is associated with metabolic abnormalities that increase the risk of type 2 diabetes and cardiovascular disease (CVD). Obese patients with a substantial accumulation of visceral adipose tissue are characterized by higher insulinemic and glycemic responses during an oral glucose challenge and a deteriorated plasma lipoprotein-lipid profile compared to normal body weight or obese individuals with low level visceral adiposity. We will use a mouse model with a primary impairment in insulin-mediated glucose flux into adipocytes to define the molecular mechanisms underlying the pathogenesis of obesity associated CVD. Male mice carrying only one functional copy of the insulin-stimulatable GLUT4 transporter (GLUT4) first display reduced GLUT4 expression specifically in white adipose tissue (WAT). Reduced GLUT4 in WAT leads to visceral obesity, progressive impairment in insulin sensitivity, altered lipid metabolism, and eventually to type 2 diabetes with associated CVD. As such, male GLUT4 mice represent an excellent model to study pathophysiological changes associated with visceral obesity in humans. Interestingly, changes in adipose cell secretory proteins, such as the adipocyte-specific Acrp30, precede the onset of measurable changes in other metabolic parameters in GLUT4 mice. We and others have demonstrated profound effects of Acrp30 on insulin resistance in liver and muscle through specific effects on carbohydrate and lipid metabolism. The objectives of this proposal are I) to understand the molecular mechanisms underlying the metabolic changes that specifically affect male, but not female GLUT4 mice or GLUT4 mice that overexpress GLUT4 in muscle; lI) to test genetically whether correction of Acrp30 downregulation in male GLUT4 will prevent or delay the onset of insulin resistance, visceral obesity and/or CVD. Additionally, we will test whether complete lack of circulating Acrp30 in Acrp30-/-mice will provoke metabolic disturbance in female GLUT4 and exacerbate disease in male GLUT4 mice; III) to assess the effects of high fat diet-induced changes in disease progression in GLUT4 compared to C57BL/6J mice; and IV) to determine transcripitional and translational changes in WAT associated with visceral obesity and alterations following treatment with thiazolidinedione insulin sensitizers in hope of identifying novel therapeutic targets. Combined, this approach will provide a comprehensive systematic characterization of a mouse model of obesity associated CVD derived from early impairment of insulin-mediated glucose flux into WAT, and directly address for the first time whether alterations in Acrp30 influence disease progression.
描述(由申请人提供):
肥胖与代谢异常有关,代谢异常会增加2型糖尿病和心血管疾病(CVD)的风险。与正常体重或具有低水平内脏脂肪的肥胖个体相比,具有内脏脂肪组织大量积聚的肥胖患者的特征在于在口服葡萄糖挑战期间较高的胰岛素血和血糖反应以及恶化的血浆脂蛋白-脂质谱。我们将使用胰岛素介导的葡萄糖流入脂肪细胞的原发性损伤的小鼠模型来确定肥胖相关CVD发病机制的分子机制。仅携带一个功能性拷贝的胰岛素刺激性GLUT 4转运蛋白(GLUT 4)的雄性小鼠首先在白色脂肪组织(WAT)中显示GLUT 4表达降低。WAT中GLUT 4的减少导致内脏肥胖、胰岛素敏感性的进行性损害、脂质代谢的改变,并最终导致2型糖尿病和相关的CVD。因此,雄性GLUT 4小鼠是研究人类内脏肥胖相关病理生理学变化的极好模型。有趣的是,脂肪细胞分泌蛋白的变化,如脂肪细胞特异性Acrp 30,先于GLUT 4小鼠其他代谢参数的可测量变化。我们和其他人已经证明了Acrp 30通过对碳水化合物和脂质代谢的特异性作用对肝脏和肌肉中的胰岛素抵抗的深远影响。该提议的目的是I)理解代谢变化的分子机制,所述代谢变化特异性地影响雄性而非雌性GLUT 4小鼠或在肌肉中过表达GLUT 4的GLUT 4小鼠; II)从遗传学上测试雄性GLUT 4中Acrp 30下调的校正是否将预防或延迟胰岛素抗性、内脏肥胖和/或CVD的发作。此外,我们将测试Acrp 30-/-小鼠中循环Acrp 30的完全缺乏是否会引起雌性GLUT 4的代谢紊乱并加重雄性GLUT 4小鼠的疾病; III)评估与C57 BL/6 J小鼠相比,高脂肪饮食诱导的GLUT 4疾病进展变化的影响;(四)确定与内脏肥胖相关的WAT转录和翻译变化以及噻唑烷二酮胰岛素增敏剂治疗后的变化,新的治疗靶点。结合,这种方法将提供一个全面的系统表征的小鼠模型的肥胖相关的CVD源自胰岛素介导的葡萄糖流量到WAT的早期损伤,并直接解决第一次在Acrp 30的改变是否影响疾病的进展。
项目成果
期刊论文数量(0)
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MAUREEN J CHARRON其他文献
MAUREEN J CHARRON的其他文献
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Altered Glucose and Lipid Metabolism in Obesity and CVD
肥胖和心血管疾病中葡萄糖和脂质代谢的改变
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$ 78.54万 - 项目类别:
Altered Glucose and Lipid Metabolism in Obesity and CVD
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6602637 - 财政年份:2003
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