Defintion of the Physiological Properties of GIP

描述(由申请人提供)：肥胖和糖尿病是复杂的多因素综合征，由遗传和环境因素相互作用发展而来。胃肠道，尤其是胃肠道调节肽是研究营养相关疾病的理想起点，因为前者代表了所有营养物质被加工和吸收的途径。除了对胰岛β细胞胰岛素释放的影响外，我们最近还在人脂肪细胞上发现了葡萄糖依赖的促胰岛素多肽(GIP)的受体。我们还发现，我们实验室开发的一种GIP特异性受体拮抗剂可以抑制这种多肽与脂肪细胞的结合。此外，我们观察到GIP抑制了异丙肾上腺素诱导的大鼠脂肪细胞的脂肪分解，这与GIP具有促进脂肪沉积的生理功能的假设一致。因此，通过拮抗脂肪细胞GIP受体，似乎有可能防止脂肪的储存，从而防止肥胖。然而，GIP对脂肪细胞功能的确切影响以及GIP在肥胖发病机制中的作用尚未确定。本项目的具体目标是：1.确定GIP受体的特征，包括受体表达的调节、脂肪细胞内的信号转导以及脂肪细胞中GIP与胰岛素的关系；2.利用啮齿动物模型确定GIP拮抗剂在肥胖发生中的作用；3.采用一种新的、灵敏的生物测定方法来测量不同啮齿动物模型中GIP的浓度，以确定GIP在正常、肥胖和糖尿病状态下的表达。这项建议中概述的研究将有助于阐明GIP在这些常见的多因素疾病的发病机制中的确切作用，以及它在调节脂肪细胞功能方面的生理作用。此外，由于GIP与胰岛素之间具有重要的功能关系，因此，深入分析调节GIP生物学特性的细胞内途径将有助于确定这两种多肽激素之间的确切关系，以及GIP的生理和病理意义及其在调节脂肪和血糖动态平衡中的重要性。最后，这些研究将使我们能够确定脂肪细胞上的GIP受体拮抗剂，以及可能在其他器官中的拮抗剂，是否可能对预防脂肪沉积和治疗肥胖有用。

DESCRIPTION (provided by applicant): Obesity and diabetic conditions are complex multifactorial syndromes that develop from an interaction between genetic and environmental factors. The GI tract and, in particular, GI regulatory peptides represent an ideal starting point for investigating nutrition-related disorders since the former represents the route by which all nutrients are processed and absorbed. In addition to its effects on islet beta-cell insulin release, we have recently identified receptors to glucose-dependent insulinotropic polypeptide (GIP) on human adipocytes. We have also found that a GIP-specific receptor antagonist developed in our laboratory inhibits binding of this peptide to fat cells. Moreover, we have observed that GIP inhibits isoproterenol-induced lipolysis in rat adipocytes, consistent with the hypothesis that GIP is functioning physiologically to enhance lipid deposition. Thus, it appears plausible that by antagonizing the adipocyte GIP receptor, the storage of lipid, and thereby obesity, might be prevented. However, neither the precise effects of GIP on adipocyte function nor the role of GIP in the pathogenesis of obesity have been determined. Specific aims of this project are to: 1. Characterize the GIP receptor, including regulation of receptor expression, intracellular signaling in adipocytes, and the relationship of GIP to insulin in fat cells; 2. Ascertain the effects of a GIP antagonist on the development of obesity using rodent models; and 3. Determine GIP expression in normal, obese, and diabetic states, employing a novel, sensitive bioassay to measure GIP concentrations in different rodent models. The studies outlined in this proposal will help clarify the precise role of GIP in the pathogenesis of these common multifactorial disorders and its physiological role in regulating fat cell function. Moreover, owing to the critical functional relationship between GIP and insulin, a detailed analysis of the intracellular pathways mediating the biological properties of GIP will facilitate the determination of the precise relationship between these two peptide hormones, as well as the physiological and pathological significance of GIP and its importance in the regulation of fat and glucose homeostasis. Finally, these studies will enable us to ascertain whether an antagonist to the GIP receptor on the adipocyte, as well as possibly in other organs, might be useful for the prevention of lipid deposition and in the treatment of obesity.