Functional Studies of the Incretin GIP Receptor in Adipocytes

描述（由申请人提供）：鉴于美国肥胖患病率超过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。在正常生理中，其他激素系统与胰岛素一起维持适当的代谢，因此，这些系统是治疗胰岛素抵抗和T2D的潜在靶点。其中一个例子是葡萄糖依赖性胰岛素多肽（GIP），这是一种肠道激素（即肠促胰岛素），是对营养物质的反应而分泌的。迄今为止，对GIP作用描述最好的是在血糖升高时促进胰岛素分泌。GIP本身不刺激胰岛素释放。GIP的功能并不局限于β细胞。GIP受体（GIPR）在脂肪细胞中表达，我们和其他人已经表明，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β细胞的葡萄糖增敏作用。在这两种情况下，GIP为靶细胞对生理刺激的反应定下基调：β细胞为葡萄糖，脂肪细胞为胰岛素。脂肪在代谢中有许多关键作用，包括葡萄糖的处理、脂肪酸的储存和调节能量代谢各个方面的激素（脂肪因子）的分泌（如瘦素、脂联素等）。因此，GIP为脂肪细胞的胰岛素反应设定基调，是适当调节代谢的基础，而GIP功能的破坏可能会导致T2D和其他胰岛素抵抗疾病的代谢改变，这一点得到了肥胖和T2D患者血清GIP水平和GIP功能改变的事实的支持。更好地了解脂肪细胞中GIP的功能可能会导致药物调节胰岛素作用作为胰岛素抵抗治疗策略的发展。在这方面的第一步是更完整地描述GIPR的生物学。尽管从人类数据和基因工程小鼠的研究中，人们对GIP在生理学中的作用了解甚多，但对脂肪细胞中的g蛋白偶联受体（GPCR）生物学知之甚少。本提案的目的是通过提供培养脂肪细胞中GIPR生物学的清晰而全面的描述来解决我们知识中的这一空白。本研究结果将为今后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，解决了该领域的迫切需要，这些结果将产生重要而持久的影响。在本项目的AIM 1中，我们将详细描述脂肪细胞中GIPR的贩运。这些

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 β-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 β-cells. In both cases GIP sets the tone of the response of the target cells to physiologic stimuli: glucose in the case of β-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 β-arrestins in GIP signaling and GIPR traffic. The GRKs and β-arrestins control the internalization/down regulation of activated GPCR's, and therefore control signaling of the GPCRs.