Elevation of the
neuropeptide corticotropin-releasing factor (CRF) in the brain is associated with a reduction of food intake and
body weight gain in normal and obese animals. A
protein that binds CRF and the related
peptide,
urocortin, with high affinity,
CRF-binding protein (CRF-BP), may play a role in energy homeostasis by inactivating members of this
peptide family in ingestive and metabolic regulatory brain regions. Intracerebroventricular administration in rats of the high-affinity CRF-BP
ligand inhibitor, rat/human CRF (6-33), which dissociates CRF 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weight gain in Zucker obese subjects and in animals withdrawn from chronic
nicotine. Chronic administration of CRF suppressed
weight gain nonselectively by 60% in both Zucker obese and lean control rats, whereas CRF-BP
ligand inhibitor treatment significantly reduced
weight gain in obese subjects, 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 secretion or elevate heart rate and blood pressure. These results provide support for the hypothesis that the CRF-BP may function within the brain to limit selected actions of CRF and/or
urocortin. Furthermore, CRF-BP may represent a novel and functionally selective target for the symptomatic treatment of excessive
weight gain associated with
obesity of multiple etiology.