CORTICOTROPIN-RELEASING FACTOR-BINDING PROTEIN LIGAND INHIBITOR BLUNTS EXCESSIVE WEIGHT-GAIN IN GENETICALLY-OBESE ZUCKER RATS AND RATS DURING NICOTINE WITHDRAWAL

Elevation of the neuropeptide corticotropin-releasing factor (CRF) in the brain is associated with a reduction of food intake and body weigh t gain in normal and obese animals, A protein that binds CRF and the r elated peptide, urocortin, with high affinity, CRF-binding protein (CR F-BP), may play a role in energy homeostasis by inactivating members o f this peptide family in ingestive and metabolic regulatory brain regi ons, Intracerebroventricular administration in rats of the high-affini ty CRF-BP ligand inhibitor, rat/human CRF (6-33), which dissociates CR F or urocortin from CRF-BP and increases endogenous brain levels of '' free'' CRF or urocortin significantly blunted exaggerated weight gain in Zucker obese subjects and in animals withdrawn from chronic nicotin e, Chronic administration of CRF suppressed weight gain nonselectively by 60% in both Zucker obese and lean control rats, whereas CRF-BP lig and inhibitor treatment significantly reduced weight gain in obese sub jects, without altering weight gain in lean control subjects, Nicotine abstinent subjects, but not nicotine-naive controls, experienced a 35 % appetite suppression and a 25% weight gain reduction following acute and chronic administration, respectively, of CRF-BP ligand inhibitor. In marked contrast to the effects of a CRF-receptor agonist, the CRF- BP ligand inhibitor did not stimulate adrenocorticotropic hormone secr etion or elevate heart rate and blood pressure, These results provide support for the hypothesis that the CRF-BP may function within the bra in to limit selected actions of CRF and/or urocortin, Furthermore, CRF -BP may represent a novel and functionally selective target for the sy mptomatic treatment of excessive weight gain associated with obesity o f multiple etiology.