Integrative Physiology of Obesity: Role of GPR160

项目总结/摘要 肽类神经递质在多种脑内调节食欲的神经元网络中起重要作用 区域，包括脑干摄食中心，如孤束核（NTS）和下丘脑。 可卡因和安非他明调节的转录物（CART）似乎是一种这样的肽， 整合外周代谢信号的介质，包括胰高血糖素样肽1和促细胞分裂素。中央 注射CART抑制多种动物模型中的食物摄入，并且CART的整体缺失导致 过量的食物摄入和增加小鼠对高脂肪饮食的敏感性。此外，中央CART 神经元似乎在全身葡萄糖稳态和膳食模式中起作用。迄今为止， CART受体仍然难以捉摸，因此限制了CART类似物对 治疗肥胖症和相关的饮食失调。CART激活下游信号级联典型 与G蛋白偶联受体（GPCRs）相关。使用我们独特的演绎推理 配体-受体匹配策略，我们鉴定了孤儿GPCR，GPR 160，作为CART的受体。在 在本研究计划中，我们建议测试以下总体假设： CART肽的生物学效应，内源性GPR 160在调节CART肽的生物学效应中起着重要作用。 食欲和代谢功能。我们将在四个具体目标中测试这些假设， 尖端的分子技术和创新的动物模型。 S.A. 1：检查CART和GPR 160之间的功能和物理关系。 S.A. 2：研究内源性GPR 160在短期调控中的作用， 食欲和新陈代谢。 S.A. 3：研究内源性GPR 160在下丘脑调节食欲和应激中的作用 激素分泌 S.A. 4.建立GPR 160缺失的遗传模型，以研究GPR 160缺失的重要性。 受体在代谢功能的长期调节。 拟议的研究将进一步评估GPR 160与 CART，建立CART和GPR 160作为短期和长期重要的配体-受体对 调节代谢功能，并产生创新的研究工具，如GPR 160-flox大鼠。

PROJECT SUMMARY/ABSTRACT Peptide neurotransmitters play important roles in the neuronal networks regulating appetite in several brain regions, including brainstem feeding centers such as the nucleus tractus solitarius (NTS) and hypothalamus. One such peptide, cocaine- and amphetamine-regulated transcript (CART), appears to act as a downstream mediator integrating peripheral metabolic signals including glucagon like peptide 1 and cholesytokinin. Central injection of CART inhibits food intake in multiple animal models and global deletion of CART leads to exaggerated food intake and increased susceptibility to a high fat diet in mice. Additionally, central CART neurons appear to play a role in whole body glucose homeostasis and meal patterning. To date, the identity of the CART receptor(s) has remained elusive, thus limiting the therapeutic potential of CART analogs for the treatment of obesity and associated eating disorders. CART activates downstream signaling cascades typical of those associated with G protein coupled receptors (GPCRs). Using our unique Deductive Reasoning Ligand-Receptor matching strategy, we identified the orphan GPCR, GPR160, to be a receptor for CART. In this Research Plan, we propose to test the overall hypotheses that activation of GPR160 is necessary for the biologic effect of CART peptides and that endogenous GPR160 plays a significant role in the regulation of appetite and metabolic function. We will test these hypotheses in four Specific Aims using a combination of cutting edge molecular techniques and innovative animal models. S.A. 1: Examine the functional and physical relationship between CART and GPR160. S.A. 2: Investigate the role of endogenous GPR160 in the short-term regulation of appetite and metabolism. S.A. 3: Investigate the role of endogenous GPR160 in the hypothalamic regulation of appetite and stress hormone secretion. S.A. 4: Establish a genetic model of GPR160 absence to investigate the importance of the receptor in the long term regulation of metabolic function. The proposed studies will further evaluate the functional and physical relationship between GPR160 and CART, establish CART and GPR160 as an important ligand-receptor pair in the short term and long term regulation of metabolic function, and produce innovative research tools, such as the GPR160-flox rat.