Peripheral activation of corticotropin-releasing factor receptor 2 inhibits food intake and alters meal structures in mice.
The orexigenic effect of urocortins (Ucns), namely Ucn 1, Ucn 2 and Ucn 3 through activation of corticotropin-releasing factor (CRF) receptors, has been well characterized after injection into the brain but not in the periphery. We examined the role of CRF receptor subtype 2 (CRF(2)) in the regulation of food intake using intraperitoneal (ip) injection of Ucns and the selective CRF(2) antagonist, astressin(2)-B, and CRF(2) knockout (-/-) mice. Meal structures were monitored using an automated episodic solid food intake monitoring system. Ucn 2 (3, 10 or 30 μg/kg, ip) induced a rapid in onset, long lasting and dose-dependent decrease (38%, 66% and 86%, respectively at 4h) of cumulative food intake after an overnight fast in mice. Ucn 3 anorexic effect was 10-times less potent. Astressin(2)-B (30 or 100 μg/kg) injected ip, but not intracerebroventricularly, blocked the inhibitory effect of ip Ucn 1 and Ucn 2 (10 μg/kg). Fasted CRF(2-/-) mice did not respond to ip Ucn 1 (10 μg/kg). Meal microstructure analysis of the 4-h re-feeding response to an overnight fast showed that Ucn 2 (10 μg/kg, ip) decreased meal size and duration, but increased meal frequency. In mice fed ad libitum, Ucn 2 (30 μg/kg) injected ip before the dark phase decreased the 4-h nocturnal meal size and duration without influencing meal frequency while the 10 μg/kg dose had no effect. These data indicate that Ucns, through peripheral CRF(2) receptor-mediated induction of satiation, inhibit the eating response to a fast more potently than the physiological nocturnal feeding in mice.
CURE Digestive Diseases Research Center, Center for Neurobiology of Stress, Department of Medicine/Digestive Diseases Division, David Geffen School of Medicine, UCLA and VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA. lixinw@ucla.edu
Lixin
L
Wang
Andreas
A
Stengel
Miriam
M
Goebel
Vicente
V
Martinez
Guillaume
G
Gourcerol
Jean
J
Rivier
Yvette
Y
Taché
D000818:Animals; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D005247:Feeding Behavior / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018019:Receptors, Corticotropin-Releasing Hormone / Q000235:genetics* / Q000378:metabolism; D054832:Urocortins / Q000008:administration & dosage / Q000378:metabolism
C101531:CRF receptor type 2; D018019:Receptors, Corticotropin-Releasing Hormone; D054832:Urocortins