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.
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