Urocortin 1 reduces food intake and ghrelin secretion via CRF₂ receptors

Abstract

it is known that urocortin 1 (UCN) acts on both corticotropinreleasing factor receptors (CRF 1 and CRF2), the mechanisms underlying UCN-induced anorexia remain unclear. In contrast, ghrelin, the endogenous ligand for the growth hormone secretagogue receptor, stimulates food intake. In the present study, we examined the effects of CRF 1 and CRF2 receptor antagonists (CRF1a and CRF2a) on ghrelin secretion and synthesis, c-fos mRNA expression in the caudal brain stem, and food intake following intracerebroventricular administration of UCN. Eight-week-old, male Sprague-Dawley rats were used after 24-h food deprivation. Acylated and des-acylated ghrelin levels were measured by enzyme-linked immunosorbent assay. The mRNA expressions of preproghrelin and c-fos were measured by real-time RT-PCR. The present study provided the following important insights into the mechanisms underlying the anorectic effects of UCN: 1) UCN increased acylated and des-acylated ghrelin levels in the gastric body and decreased their levels in the plasma; 2) UCN decreased preproghrelin mRNA levels in the gastric body; 3) UCN-induced reduction of plasma ghrelin and food intake were restored by CRF 2a but not CRF1a; 4) UCN-induced increase of c-fos mRNA levels in the caudal brain stem containing the nucleus of the solitary tract (NTS) was inhibited by CRF 2a; and 5) UCN-induced reduction of food intake was restored by exogenous ghrelin and rikkunshito, an endogenous ghrelin secretion regulator. Thus, UCN increases neuronal activation in the caudal brain stem containing NTS via CRF 2 receptors, which may be related to UCN-induced inhibition of both ghrelin secretion and food intake.corticotropin-releasing factor receptors; dorsal vagal complex; rikkunshito; digestive system hormone; anorexia STRESSFUL LIFE EVENTS have been associated with the onset or symptom exacerbation of several functional gastrointestinal disorders including functional dyspepsia and irritable bowel syndrome (24). Corticotropin-releasing factor (CRF) is a key mediator in the central nervous system and is secreted as an adaptive response to stress. In rodents, central CRF administration induces stress-like behaviors, including increased depression, decreased rearing activity, and suppression of food intake (5, 50). Urocortin 1 (UCN), a member of the mammalian CRF family, bears 45% sequence identity to CRF and acts as an endogenous ligand for CRF receptors (49). Although CRF and UCN mediate their actions through the activation of CRF 1 and CRF 2 receptors, CRF and UCN display different binding affinities for these receptors. CRF preferentially binds to CRF 1 receptors, whereas UCN shows high affinity for both receptors; we therefore believe that UCN is useful for examining the actions of both CRF 1 and CRF 2 receptors. Central UCN administration suppresses feeding in rats and mice, and the suppression was shown to be at least partly CRF 2 mediated in studies that used selective antagonists (7) or antisense oligonucleotides (38). In addition, the initial effect of food intake in...

Decreased plasma ghrelin contributes to anorexia following novelty stress

“…However, pharmacological maintenance of endogenous circulatory hormones such as ghrelin is extremely difficult in mice and other rodents. RKT has also been studied using facilitated ghrelin secretion to clarify the role of endogenous ghrelin (3,52). Although RKT is crude, a single dose of RKT stabilizes endogenous ghrelin concentration and maintains the level (for ϳ6 h) (unpublished data).…”

Pathophysiologic Basis of Anorexia: Focus on the Interaction between Ghrelin Dynamics and the Serotonergic System

“…50) There are several reports showing that the administration of Ucn1 to humans and rodents reduces plasma ghrelin concentrations. [51][52][53] In addition, Ucn1-induced decreases in plasma ghrelin and food intake were restored by CRFR2 but not CRFR1. 53) We have recently determined that CRFR1 is also involved in the regulation of ghrelin secretion.…”

CRF and urocortin peptides as modulators of energy balance and feeding behavior during stress

“…In ad libitum fed rats, intracerebroventricular (icv) injection of CRF (Spina et al, 1996), Ucn 1 (Spina et al, 1996; Yakabi et al, 2011), Ucn 2 (Ohata and Shibasaki, 2004), and Ucn 3 (Ohata and Shibasaki, 2004) decreases dark phase food intake. At the lowest icv doses, Ucn 1 and Ucn 2 decrease food intake without inducing conditioned taste aversion or visceral illness (Benoit et al, 2000; Inoue et al, 2003; Zorrilla et al, 2004).…”