Functional Studies of the Incretin GIP Receptor in Adipocytes
脂肪细胞中肠促胰岛素 GIP 受体的功能研究
基本信息
- 批准号:8585058
- 负责人:
- 金额:$ 36.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-12-01 至 2016-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdipocytesAdipose tissueAffectArrestinsBehaviorBeta CellBiological ModelsBiologyBlood GlucoseCellsDevelopmentDown-RegulationEndocrineEndocrine systemEnergy MetabolismFatty AcidsFatty acid glycerol estersFoundationsFutureG Protein-Coupled Receptor GenesG Protein-Coupled Receptor SignalingG protein coupled receptor kinaseG-Protein-Coupled ReceptorsGLUT4 geneGenetically Engineered MouseGlucoseGoalsHormonesHumanInsulinInsulin ResistanceKnowledgeLeadLeptinLigandsLinkMass Spectrum AnalysisMembrane Protein TrafficMetabolicMetabolismMolecularMutationNon-Insulin-Dependent Diabetes MellitusNutrientObesityPancreasPhospho-Specific AntibodiesPhosphorylationPhosphotransferasesPhysiologicalPhysiologyPrevalencePublic HealthQualifyingRegulationRoleSerumSignal TransductionSmall Interfering RNAStimulusStructureSystemTissuesWorkadipokinesadiponectinbasegastric inhibitory polypeptide receptorglucose disposalglucose transporthuman datainsulin secretioninsulin sensitivityinsulin sensitizing drugspublic health relevancereceptorreceptor functionresponsetrafficking
项目摘要
DESCRIPTION (provided by applicant): Given the US prevalence rate of obesity of over 30%, insulin resistance and type 2 diabetes (T2D) are two looming public health issues. In normal physiology other hormonal systems work with insulin to maintain proper metabolism, and consequently, these systems are potential targets for the treatment of insulin resistance and T2D. One such example is Glucose-dependent Insulinotropic Polypeptide (GIP), a gut hormone (so called incretin) secreted in response to nutrients. To date, the best-described role GIP is to promote the amount of insulin secreted for a given rise in blood glucose. GIP itself does not stimulate insulin release. The functions of GIP are not limited to ¿-cells. GIP Receptors (GIPR) are expressed in adipocytes, and we, and others, have shown that GIP stimulation increases the sensitivity of adipocytes to insulin. Conceptually, this insulin-sensitizing effect is similar o the glucose-sensitizing effects of GIP on ¿-cells. In both cases GIP sets the tone of the response of the target cells to physiologic stimuli: glucose in the case of ¿-cells and insulin in adipocytes. Adipose has a number of critical roles in metabolism including disposal of glucose, storage of fatty acids and the secretion of hormones (adipokines) that regulate various aspects of energy metabolism (e.g., leptin, adiponectin, etc.). Therefore, GIP setting the tone of insulin response of adipocytes is fundamental for the proper regulation of metabolism, and disruption of GIP functions likely contribute to metabolic alterations in T2D and other insulin resistant conditions, which is supported by the facts that serum GIP levels and GIP function have been shown to be altered in obesity and T2D. A better understanding of the function of GIP in adipocytes might lead to the development of strategies to pharmacologically modulate insulin action as a treatment for insulin resistance. A first step in this regard would be a more complete description of the biology of the GIPR. Despite the great deal that is known about the role of GIP in physiology from human data and studies of genetically engineered mice, little is known about the biology of the GIPR, a G-Protein Coupled Receptor (GPCR) biology in adipocytes. The objective of this proposal is to address this gap in our knowledge by providing a clear and comprehensive description of the biology of GIPR in cultured adipocytes. The results of this proposal will establish a foundation and framework for future physiology studies. Consequently, these cellular studies, which I believe my lab is nearly uniquely qualified to perform, address an immediate need for the field and these results will have an important and lasting impact. In AIM 1 of this project we will characterize, in detail, the trafficking of the GIPR in adipocytes. These
studies are based on my lab's expertise, in large part developed through studies of the insulin-regulated GLUT4 glucose transport, in the studies of regulated membrane protein trafficking. In AIM 2 we will define phosphorylation of GIPR and determine the impact of receptor phosphorylation on GIPR trafficking and GIP signaling. In the AIM 3 we will characterize the roles of GPCR kinases (GRKs) and ¿-arrestins in GIP signaling and GIPR traffic. The GRKs and ¿-arrestins control the internalization/down regulation of activated GPCR's, and therefore control signaling of the GPCRs.
描述(申请人提供):鉴于美国肥胖率超过30%,胰岛素抵抗和2型糖尿病(T2D)是两个迫在眉睫的公共卫生问题。在正常生理学中,其他激素系统与胰岛素一起工作以维持适当的新陈代谢,因此,这些系统是治疗胰岛素抵抗和T2D的潜在靶点。一个这样的例子是葡萄糖依赖型促胰岛素多肽(GIP),这是一种对营养物质做出反应而分泌的肠道激素(所谓的胰岛素素)。到目前为止,GIP被描述得最好的作用是促进给定血糖升高的胰岛素分泌量。GIP本身并不刺激胰岛素的释放。GIP的功能并不局限于细胞。GIP受体(GIPR)在脂肪细胞中表达,我们和其他人已经证明GIP刺激增加了脂肪细胞对胰岛素的敏感性。从概念上讲,这种胰岛素增敏作用类似于GIP对细胞的葡萄糖增敏作用。在这两种情况下,GIP都设定了目标细胞对生理刺激的反应基调:细胞中的葡萄糖和脂肪细胞中的胰岛素。脂肪在新陈代谢中有许多关键作用,包括葡萄糖的处理、脂肪酸的储存和激素(脂肪因子)的分泌,这些激素调节能量代谢的各个方面(如瘦素、脂联素等)。因此,GIP调节脂肪细胞胰岛素反应的基调是正确调节代谢的基础,而GIP功能的破坏可能导致T2D和其他胰岛素抵抗条件下的代谢变化,这一事实得到了肥胖和T2D的血清GIP水平和GIP功能改变的事实的支持。更好地了解GIP在脂肪细胞中的功能可能会导致开发药物调节胰岛素作用的策略,作为治疗胰岛素抵抗的方法。这方面的第一步将是更全面地描述全球知识产权制度的生物学特征。尽管从人类数据和转基因小鼠的研究中已经知道了大量关于GIP在生理学中的作用,但对GIPR的生物学知之甚少,GIPR是脂肪细胞中的一种G蛋白偶联受体(GPCR)生物学。这项建议的目的是通过对培养的脂肪细胞中GIPR的生物学提供清晰和全面的描述来解决我们知识中的这一差距。这一建议的结果将为未来的生理学研究奠定基础和框架。因此,这些细胞研究,我相信我的实验室几乎是唯一有资格进行的,满足了该领域的迫切需求,这些结果将产生重要和持久的影响。在本项目的目标1中,我们将详细描述GIPR在脂肪细胞中的转运。这些
研究是基于我的实验室的专业知识,在很大程度上是通过研究胰岛素调节的GLUT4葡萄糖运输,在调节膜蛋白运输的研究中发展起来的。在AIM 2中,我们将定义GIPR的磷酸化,并确定受体磷酸化对GIPR转运和GIP信号转导的影响。在AIM 3中,我们将描述GPCRK(GRKs)和?-arrestins在GIP信号和GIPR流量中的作用。GRK和阻滞素控制激活的GPCRs的内化/下调,从而控制GPCRs的信号转导。
项目成果
期刊论文数量(0)
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{{ truncateString('TIMOTHY E MCGRAW', 18)}}的其他基金
Insulin control of GLUT4 traffic to the plasma membrane of adipocytes
胰岛素控制 GLUT4 向脂肪细胞质膜的运输
- 批准号:
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- 资助金额:
$ 36.76万 - 项目类别:
Insulin control of GLUT4 traffic to the plasma membrane of adipocytes
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10224692 - 财政年份:2020
- 资助金额:
$ 36.76万 - 项目类别:
Insulin control of GLUT4 traffic to the plasma membrane of adipocytes
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10438682 - 财政年份:2020
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Insulin control of GLUT4 traffic to the plasma membrane of adipocytes
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- 批准号:
10655330 - 财政年份:2020
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$ 36.76万 - 项目类别:
GIP receptor: The role of post-activation receptor behavior for the incretin effect
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9976501 - 财政年份:2018
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GIP receptor: The role of post-activation receptor behavior for the incretin effect
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Functional Studies of the Incretin GIP Receptor in Adipocytes
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8963463 - 财政年份:2012
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$ 36.76万 - 项目类别:
Functional Studies of the Incretin GIP Receptor in Adipocytes
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