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

Abstract

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.

RLN3/RXFP3 Signaling in the PVN Inhibits Magnocellular Neurons via M-like Current Activation and Contributes to Binge Eating Behavior

“…The PVN is a hub of central homeostatic control, modulating hormonal release and autonomic responses. Current data, together with previous reports ( McGowan et al, 2005 ; Ganella et al, 2013a ; Lenglos et al, 2013 ; Calvez et al, 2015 , 2016b ; Kania et al, 2017 ; de Ávila et al, 2018 ) provide extensive evidence that RLN3/RXFP3 signaling in the PVN constitutes a novel addition to our understanding of the neural circuitry governing physiological food intake, as well as abnormal eating behavior. Moreover, as OXT- and AVP-synthesizing MNCs control fundamental biological processes, including water balance, reproduction, nociception, and a variety of social and parenting behaviors (for review, see Gimpl and Fahrenholz, 2001 ; Koshimizu et al, 2012 ), a direct inhibitory action of RLN3 on these neurons has broad behavioral implications.…”

Central relaxin-3 receptor (RXFP3) activation impairs social recognition and modulates ERK-phosphorylation in specific GABAergic amygdala neurons

“…Previous studies have described robust effects of icv infusion of RXFP3 agonists within 20 min post-infusion (Ryan et al 2013a;Albert-Gascó et al 2017;de Ávila et al 2018). Thus, we designed a schedule in which icv infusion of the agonist, RXFP3-A2 or vehicle, was administered 20 min prior to the social or preference tests.…”

Differential Level of RXFP3 Expression in Dopaminergic Neurons Within the Arcuate Nucleus, Dorsomedial Hypothalamus and Ventral Tegmental Area of RXFP3-Cre/tdTomato Mice

“…Relaxin-family peptide 3 receptor (RXFP3) is a G-proteincoupled receptor that is primarily expressed in the brain, and is activated by its cognate neuropeptide, relaxin-3 (Ma et al, 2017). Pharmacological manipulation of RXFP3 alters feeding behaviors in rodents, identifying RXFP3 as a promising therapeutic target for treating obesity and other eating disorders (McGowan et al, 2005(McGowan et al, , 2006Ganella et al, 2012Ganella et al, , 2013Smith et al, 2014;De Ávila et al, 2018). For example, acute intracerebroventricular (ICV) administration of human relaxin-3 increased food consumption in rats (McGowan et al, 2005).…”