Functional Studies of the Incretin GIP Receptor in Adipocytes

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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.