Systemic urocortin 2, but not urocortin 1 or stressin 1 ‐A, suppresses feeding via CRF 2 receptors without malaise and stress

BACKGROUND AND PURPOSE Infusion of corticotropin‐releasing factor (CRF)/urocortin (Ucn) family peptides suppresses feeding in mice. We examined whether rats show peripheral CRF/Ucn‐induced anorexia and determined its behavioural and pharmacological bases. EXPERIMENTAL APPROACH Male Wistar rats ( n = 5–12 per group) were administered (i.p.) CRF receptor agonists with different subtype affinities. Food intake, formation of conditioned taste aversion and corticosterone levels were assessed. In addition, Ucn 1‐ and Ucn 2‐induced anorexia was studied in fasted CRF 2 knockout ( n = 11) and wild‐type ( n = 13) mice. KEY RESULTS Ucn 1, non‐selective CRF receptor agonist, reduced food intake most potently (∼0.32 nmol·kg −1 ) and efficaciously (up to 70% reduction) in fasted and fed rats. The peptides' rank‐order of anorexic potency was Ucn 1 ≥ Ucn 2 > >stressin 1 ‐A > Ucn 3, and efficacy, Ucn 1 > stressin 1 ‐A > Ucn 2 = Ucn 3. Ucn 1 reduced meal frequency and size, facilitated feeding bout termination and slowed eating rate. Stressin 1 ‐A (CRF 1 agonist) reduced meal size; Ucn 2 (CRF 2 agonist) reduced meal frequency. Stressin 1 ‐A and Ucn 1, but not Ucn 2, produced a conditioned taste aversion, reduced feeding efficiency and weight regain and elicited diarrhoea. Ucn 1, but not Ucn 2, also increased corticosterone levels. Ucn 1 and Ucn 2 reduced feeding in wild‐type, but not CRF 2 knockout, mice. CONCLUSIONS AND IMPLICATIONS CRF 1 agonists, Ucn 1 and stressin 1 ‐A, reduced feeding and induced interoceptive stress, whereas Ucn 2 potently suppressed feeding via a CRF 2 ‐dependent mechanism without eliciting malaise. Consistent with their pharmacological differences, peripheral urocortins have diverse effects on appetite.