Human Urocortin 2, a Corticotropin-Releasing Factor (CRF)₂Agonist, and Ovine CRF, a CRF₁Agonist, Differentially Alter Feeding and Motor Activity

Abstract

Two corticotropin-releasing factor (CRF) receptor families have been identified (CRF 1 and CRF 2 ). Whereas anxiogenic-like roles for the CRF 1 receptor have been identified, behavioral functions of the CRF 2 receptor remain obscure. Urocortin 2 (Ucn 2), a CRF-related peptide that selectively binds CRF 2 receptors, was recently identified and recognized for its central anorectic properties. The present study tested the hypothesis that the anorexigenic mode of action of Ucn 2 differed from that of ovine CRF (oCRF), a preferential CRF 1 receptor agonist. The behavioral effects of intracerebroventricular administration of Ucn 2 were compared with those of oCRF in nondeprived male Wistar rats (n ϭ 102). Ucn 2 reduced 6-h food and water intake at doses that did not induce visceral illness (0.1, 1, and 10 g), as indicated by kaolin intake. Ucn 2 retained its potent anorectic activity in rats receiving a highly palatable cafeteria diet, preferentially reducing intake of carbohydrate (CHO)-rich items while sparing intake of mixed-fat/CHO items. In contrast to Ucn 2, oCRF (10 g) suppressed 6-h intake of cafeteria diet-fed rats without regard to macronutrient composition. Rather, oCRF most potently suppressed intake of preferred food items. Whereas oCRF had short-onset motor-activating effects, Ucn 2 had nondose-dependent, delayed-onset motor-suppressing effects. Thus, central infusion of a CRF 2 receptor agonist suppressed intake of both bland and palatable diets without inducing behavioral arousal or malaise, and the profile of anorexigenic effects qualitatively differed from those of a CRF 1 receptor agonist. The results suggest the existence of distinct forms of CRF 1 -and CRF 2 -mediated anorexia.

Stimulation of Lateral Septum CRF2Receptors Promotes Anorexia and Stress-Like Behaviors: Functional Homology to CRF1Receptors in Basolateral Amygdala

“…This hypothesis is in contradiction to previous conceptualizations of the role of the CRF 2 receptor in ingestive behavior, which have argued that stimulation of this receptor reduces feeding without inducing anxiety-like effects (Zorrilla et al, , 2004, a notion that is based primarily on the finding that intracerebroventricular administration of urocortin2 and urocortin3 can cause delayed reductions in stress-like responses (Spina et al, 1996;Valdez et al, 2002Valdez et al, , 2003Valdez et al, , 2004Venihaki et al, 2004). Yet, multiple studies, in addition to the present findings, indicate that particularly when administered site-specifically into extrahypothalamic regions including the LS, UCN or urocortin2 promotes stress-like behaviors through the activation of CRF 2 receptors (Moreau et al, 1997;Radulovic et al, 1999;Pelleymounter et al, 2000Pelleymounter et al, , 2002Pelleymounter et al, , 2004Spina et al, 2002;Risbrough et al, 2003;Henry et al, 2006).…”

Differential blockade of CRF-evoked behaviors by depletion of norepinephrine and serotonin in rats

“…The attenuation of all behaviors by blockade of the CRF 1 receptor using antalarmin further supported mediation by the CRF 1 receptor. Moreover, no effect of CRF 2 receptor stimulation with the selective agonist urocortin II was observed on any of the behaviors, with doses that are reported to affect feeding behvior (Zorilla et al, 2004). The role of CRF 1 receptors in grooming is supported by evidence from previous investigations (Bressers et al 1995;de Groote et al 2005;Drago et al 1999;Lumley et al 2001;Ohata and Shibasaki 2004).…”

Delayed Satiety-Like Actions and Altered Feeding Microstructure by a Selective Type 2 Corticotropin-Releasing Factor Agonist in Rats: Intra-Hypothalamic Urocortin 3 Administration Reduces Food Intake by Prolonging the Post-Meal Interval

“…A caveat to this conclusion is that Ucn 3's anorectic effects are delayed, and the formation of a CTA depends on temporal proximity between the conditioned stimulus and the aversive drug state, so it would be useful to evaluate Ucn 3's actions in a time-insensitive measure of malaise. In this vein, the related CRF 2 agonist Ucn 2 did not increase kaolin clay intake (pica), an unconditioned measure of visceral illness at doses through 10 mg (Zorrilla et al, 2004). Still, it cannot be ruled out that aversive, 'non-visceral' actions of high doses of Ucn 2 (Inoue et al, 2003) that promoted a CTA might be shared by high doses of Ucn 3.…”

“…We and others found that i.c.v. Ucn 2 reduced nocturnal food intake (Zorrilla et al, 2004), beginning 3-6 h postinjection in nondeprived rats (Inoue et al, 2003;Ohata and Shibasaki, 2004;de Groote et al, 2005) or mice (Reyes et al, 2001). Ucn 3 (i.c.v.)…”