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Endocrinology Vol. 141, No. 8 2715-2724
Copyright © 2000 by The Endocrine Society

ARTICLES

Modulation of Urocortin-Induced Hypophagia and Weight Loss by Corticotropin-Releasing Factor Receptor 1 Deficiency in Mice1

Margaret J. Bradbury, Mary I. McBurnie, Derek A. Denton, Kuo-Fen Lee and Wylie W. Vale2

The Clayton Foundation Laboratories for Peptide Biology (M.J.B., K.-F.L., W.W.V.), The Salk Institute, La Jolla, California 92037; and The Howard Florey Institute of Experimental Physiology and Medicine (M.I.M., D.A.D.), University of Melbourne, Parkville, Victoria, 3052, Australia

Address all correspondence and requests for reprints to: Wylie Vale, Ph.D., Clayton Foundation Laboratories for Peptide Biology, 10010 North Torrey Pines Road, La Jolla, California 92037. E-mail: vale{at}salk.edu

Intracerebroventricular injection of CRF or urocortin (Ucn) reduces appetite and body weight. CRFR1 and CRFR2, the receptors for CRF and Ucn, are expressed in neurons associated with appetite-control and metabolism, but their relative contributions in mediating CRF- or Ucn-induced hypophagia and weight loss are not known. We used homozygous mice lacking CRFR1 (CRFR1-/-) and wild-type littermates to determine the role of CRFR1 in mediating the changes in food intake and body weight following intracerebroventricular administration of Ucn. CRFR1-/- mice, which are glucocorticoid deficient, were given corticosterone in their drinking water to induce diurnal variations in circulating corticosterone. A 7-day intracerebroventricular infusion of Ucn transiently suppressed ad libitum food intake equally in CRFR1-/- and wild-type mice. Body weight reduction during Ucn infusion paralleled food intake in wild-type mice, but persisted throughout the infusion in CRFR1-/- mice. After food-deprivation, acute intracerebroventricular injection of Ucn suppressed food intake for 1.5 h in wild-type mice. By contrast, CRFR1-/- mice did not respond to Ucn 1.5 h after injection. At later time points, Ucn suppressed food intake equally in both genotypes. The distinct time courses of CRF-receptor-induced hypophagia suggest that separate pathways act cooperatively to adjust food intake during challenges to homeostasis.




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