Role of the CRF2 Receptor in Ingestive Behavior

CRF2 受体在摄入行为中的作用

• 批准号: 6797182
• 负责人: ERIC P ZORRILLA
• 金额: $ 18.77万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6797182
• 关键词: anorexic agent; appetite; behavior test; corticotropin releasing factor; dietary restriction; eating; hormone receptor; hunger; laboratory rat; neurochemistry; neuropharmacology; obesity; overeating; protein structure function; satiations; stress

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.

描述（由申请人提供）： 在美国，超重和肥胖现象十分普遍。肥胖和超重是主要的公共卫生问题，每年导致全国约 30 万人死亡，造成 1,170 亿美元的医疗费用。长期服用厌食药是一种行之有效的控制体重的方法。为了确定药物靶点，一种有前途的方法是更好地了解进食行为的神经化学。虽然人们早就知道促肾上腺皮质激素释放因子 (CRF) 家族的肽在集中给药时会减少食物摄入量，但对其作用机制仍知之甚少。 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，CRF1和CRF2_受体在摄食调节中的相对作用仍然难以捉摸。大脑 CRF1 受体介导身体的应激反应。因此，CRF1介导的厌食症可能简单地反映了继发于应激状态的非特异性摄食抑制。这种担忧限制了 CRF1 受体作为肥胖药物靶点的可行性。然而，一些发现激发了人们对 CRF2 受体在食欲调节中的作用的兴趣。不幸的是，目前还没有 CRF2 受体的选择性配体，因此无法对其在摄食行为中的作用进行药理学表征。最近，两个研究小组独立鉴定了编码哺乳动物 CRF/Ucn 相关肽的基因，这些基因在进化上彼此不同，也与 CRF 和 Ucn 不同。它们是第一个已知的直接、高选择性 CRF2 受体激动剂。其中，鼠 Ucn III 是选择性最强的。与此同时，第一个有效的、高选择性的、长效的 CRF2 受体拮抗剂——astressin2-B——已经开发出来。目前的提案使用这些工具来探测大脑 CRF2 受体的摄取功能。此外，尚不清楚CRF2受体是否会承担CRF1受体激活的不利后果。 CRF2 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，并更好地了解 CRF2 受体在进食行为中的作用。