Differential effects of relaxin-3 and a selective relaxin-3 receptor agonist on food and water intake and hypothalamic neuronal activity in rats.

The neuropeptide relaxin-3 (RLN3) binds with high affinity to its cognate receptor, relaxin-family peptide receptor 3 (RXFP3), and with lower affinity to RXFP1, the cognate receptor for relaxin. Intracerebroventricular (icv) administration of RLN3 in rats strongly increases food and water intake and alters the activity of the hypothalamic-pituitary-adrenal (HPA) and gonadal (HPG) axes, but the relative involvement of RXFP3 and RXFP1 in these effects is not known. Therefore, the effects of icv administration of equimolar (1.1 nmol) amounts of RLN3 and the RXFP3-selective agonist RXFP3-A2 on food and water intake, plasma levels of corticosterone, testosterone, and oxytocin and c-fos mRNA expression in key hypothalamic regions in male rats were compared. Food intake was increased by both RLN3 and RXFP3-A2, but the orexigenic effects of RXFP3-A2 were significantly stronger than RLN3, 30 and 60min after injection. Water intake and plasma corticosterone and testosterone levels were significantly increased by RLN3, but not by RXFP3-A2. Conversely, RXFP3-A2 but not RLN3 decreased oxytocin plasma levels. RLN3, but not RXFP3-A2, increased c-fos mRNA levels in the parvocellular (PVNp) and magnocellular (PVNm) paraventricular and supraoptic (SON) hypothalamic nuclei, in the ventral medial preoptic area (MPAv), and in the organum vasculosum of the lamina terminalis (OVLT). A significant increase in c-fos mRNA expression was induced in the perifornical lateral hypothalamic area (LHApf) by RLN3 and RXFP3-A2. These results suggest that RXFP1 is involved in the RLN3 stimulation of water intake and activation of the HPA and HPG axes. The reduced food intake stimulation by RLN3 compared to RXFP3-A2 may relate to activation of both orexigenic and anorexigenic circuits by RLN3.

Hypothalamic expression of urocortin 3 and the type 2 corticotropin-releasing factor receptor is regulated according to feeding state in lean but not obese Zucker rats.

Urocortin 3 (Ucn3) is an anorexigenic neuropeptide with high affinity for the type 2 corticotropin-releasing factor receptor (CRF2-R). How the expression of hypothalamic Ucn3 is regulated by fasting and refeeding in genetically obese (fa/fa) Zucker rats is not known. Obese Zucker rats develop early hyperphagia associated with low expression of CRF2-R in the ventromedial hypothalamic nucleus (VMH) in this phenotype. Although lean (Fa/?) Zucker rats have strong basal expression of CRF2-R in the VMH, and normally consume less food compared to their obese littermates, at the beginning of refeeding, the lean rats ingested almost the same amount of food as the obese animals. The present study was designed to investigate the dynamics of the expression of CRF2-R and Ucn3 in the brain of lean and obese Zucker rats fed ad libitum, food-deprived for 48 h, or refed for 1 and 24 h. The levels of expression of Ucn3 mRNA were analyzed in the rostral perifornical hypothalamus (rPFH) and dorsal medial amygdala (MeD), and CRF2-R mRNA in the VMH and lateral septum (LS) using in situ hybridization. The results showed that in the ad libitum-fed state, both phenotypes had comparable levels of expression of rPFH Ucn3, but the obese rats had lower levels of expression of VMH CRF2-R. Food deprivation decreased hypothalamic expression of Ucn3 and CRF2-R in lean but not obese rats. One hour of refeeding triggered expression of rPFH Ucn3 but not VMH CRF2-R in lean rats, and at 24 h of refeeding the levels of hypothalamic expression of Ucn3 and CRF2-R returned to those seen in the ad libitum-fed state in both phenotypes. In the LS, the levels of expression of CRF2-R were not affected by feeding and phenotype. In the MeD, the Ucn3 transcript increased by food deprivation in obese but not lean rats. Therefore, the increase of Ucn3 expression in the MeD in obese food-deprived rats may reflect stronger behavioral effects of food deprivation in this phenotype. The hypothalamic expression of Ucn3 and CRF2)-R was modulated by the feeding states in lean but not obese rats. The low levels of VMH CRF2-R may limit anorexigenic Ucn3 effects in the obese phenotype. The low VMH CRF2-R levels at the beginning of refeeding in lean rats may allow them to ingest a considerable amount of food regardless of the rapidly increased expression of rPFH Ucn3 by refeeding in this phenotype. This article is part of a Special Issue entitled 'Central Control of Food Intake'.