Role of the CRF2 Receptor in Ingestive Behavior

描述（由申请人提供）： 超重和肥胖在美国是一种流行病。肥胖和超重是主要的公共卫生问题，每年造成约30万人死亡，全国卫生费用达1170亿美元。长期服用减食欲药是一种行之有效的控制体重的方法。为了确定药物靶点，一个有希望的方法是更好地理解摄食行为的神经化学。虽然人们早就知道，促肾上腺皮质激素释放因子（CRF）家族的肽减少食物摄入量时，中央给予，其作用机制仍然知之甚少。CRF和尿皮质素是CRF肽家族中第一个和第二个被鉴定的哺乳动物成员。这些肽中的每一种都是非选择性的，以相似的亲和力结合哺乳动物CRF受体。由于CRF受体的重叠分布和可用肽配体的非选择性，CRF 1和CRF 2受体在摄食调节中的相对作用仍然难以捉摸。脑CRF 1受体介导身体应激样反应。因此，CRF 1介导的厌食症可能只是反映了继发于应激样状态的非特异性摄食抑制。这种担忧限制了CRF 1受体作为肥胖症药物靶点的可行性。然而，一些发现激发了人们对CRF 2受体在食欲调节中的作用的兴趣。不幸的是，CRF 2受体的选择性配体尚未获得，排除了其在摄食行为中的作用的药理学表征。最近，两个小组独立地鉴定了编码哺乳动物CRF/Ucn相关肽的基因，这些肽在进化上彼此不同，也不同于CRF和Ucn。它们是第一个已知的直接的、高选择性的CRF 2受体激动剂。其中，鼠Ucn III是最有效的选择性。与此同时，第一个有效的，高选择性的，长效的CRF 2受体拮抗剂-astressin 2-B -已经开发出来。目前的提议使用这些工具来探测脑CRF 2受体的摄取功能。此外，尚不清楚CRF 2受体是否与CRF 1受体活化具有相同的不良后果。CRF 2介导的厌食症的中心作用位点和生理作用也仍然未知。拟议的研究也将解决这些问题，以更好地了解CRF 2受体在摄食行为中的作用。

DESCRIPTION (provided by applicant): The prevalence of overweight and obesity in the United States is epidemic. Obesity and overweight are major public health problems, annually responsible for approximately 300,000 deaths and health costs of $117 billion nationally. Long-term administration of anorectics is one proven approach to weight control. To identify drug targets, a promising approach is to understand better the neurochemistry of feeding behavior. While it has long been known that peptides of the corticotropin-releasing factor (CRF) family reduce food intake when given centrally, their mechanisms of action remain poorly understood. CRF and urocortin were the first and second mammalian members of the CRF peptide family to be identified. Each of these peptides is non-selective, binding both mammalian CRF receptors with similar affinities. Because of the overlapping distribution of CRF receptors and the non-selectivity of available peptide ligands, the relative roles of CRF1 and CRF2_ receptors in the regulation of feeding have remained elusive. Brain CRF1 receptors mediate bodily stress-like responses. As such, CRFl-mediated anorexia may simply reflect non-specific feeding suppression secondary to a stress-like state. This concern limits the viability of the CRF1 receptor as a drug target for obesity. Several findings, however, have spurred interest in the role of the CRF2 receptor in appetite regulation. Unfortunately, selective ligands for the CRF2 receptor have not been available, precluding pharmacological characterization of its role in feeding behavior. Recently, two groups independently identified genes encoding mammalian CRF/Ucn-related peptides that are evolutionarily distinct from one another as well as from CRF and Ucn. They are the first known direct, highly selective CRF2 receptor agonists. Of them, murine Ucn III is the most selectively potent. Contemporaneously, the first potent, highly selective, and long acting CRF2 receptor antagonist -- astressin2-B -- has been developed. The present proposal uses these tools to probe the ingestive functions of brain CRF2 receptors. In addition, it is not clear whether the CRF2 receptor shares the adverse consequences of CRF1 receptor activation. The central sites of action and physiologic role for CRF2-mediated anorexia also remain unknown. The proposed studies will address these questions as well to understand better the role of the CRF2 receptor in feeding behavior.