Hypothalamic mapping of orexigenic action and Fos-like immunoreactivity following relaxin-3 administration in male Wistar rats

Abstract

Bloom SR. Hypothalamic mapping of orexigenic action and Fos-like immunoreactivity following relaxin-3 administration in male Wistar rats. Am J Physiol Endocrinol Metab 292: E913-E919, 2007. First published November 28, 2006; doi:10.1152/ajpendo.00346.2006.-The insulin superfamily, characterized by common disulphide bonds, includes not only insulin but also insulin-like peptides such as relaxin-1 and relaxin-3. The actions of relaxin-3 are largely unknown, but recent work suggests a role in regulation of food intake. Relaxin-3 mRNA is highly expressed in the nucleus incertus, which has extensive projections to the hypothalamus, and relaxin immunoreactivity is present in several hypothalamic nuclei. In the rat, relaxin-3 binds and activates both relaxin family peptide receptor 1, which also binds relaxin-1, and a previously orphaned G protein-coupled receptor, RXFP3. These receptors are extensively expressed in the hypothalamus. The aims of these studies were twofold: 1) map the hypothalamic site(s) of the orexigenic action of relaxin-3 and 2) examine the site(s) of neuronal activation following central relaxin-3 administration. After microinjection into hypothalamic sites, human relaxin-3 (H3; 180 pmol) significantly stimulated 0-to 1-h food intake in the supraoptic nucleus (SON), arcuate nucleus (ARC), and the anterior preoptic area (APOA) [SON 0.4 Ϯ 0.2 (vehicle) vs. 2.9 Ϯ 0.5 g (H3), P Ͻ 0.001; ARC 0.7 Ϯ 0.3 (vehicle) vs. 2.7 Ϯ 0.2 g (H3), P Ͻ 0.05; and APOA 0.8 Ϯ 0.1 (vehicle) vs. 2.2 Ϯ 0.2 g (H3), P Ͻ 0.05]. Cumulative food intake was significantly increased Յ8 h following administration into the SON and 4 h into the APOA. A significant increase in Fos-like immunoreactivity was seen in the SON following central relaxin-3 administration. Relaxin-3 stimulates feeding in several hypothalamic nuclei, and these studies provide additional support for relaxin-3 as an important peptide in appetite regulation. relaxin family peptide receptor 3; appetite; supraoptic nucleus; arcuate nucleus THE INSULIN SUPERFAMILY of peptides is characterized by a common structure typified by one intrachain and two interchain disulphide bridges (20). In addition to insulin and insulin-like growth factors, the family also includes several insulin-like peptides: relaxin-1, relaxin-3, and insulin-like peptide-3, -4, -5, and -6 (5). Classical relaxin (H2 in humans, M1 in mice, and R1 in rats, referred to as relaxin-1 for clarity) is highly expressed in the female reproductive tract (36). Its primary roles appear to be in reproduction and parturition, but peripheral relaxin-1 also has marked effects on water intake (37, 45). The physiological role of the more recently described relaxin-3 remains largely unknown. In contrast to relaxin-1, relaxin-3 is expressed at the greatest levels in the central nervous system and primarily in the nucleus incertus (NI) of the brainstem (9, 44). This area has extensive projections to the forebrain, in particular to the hypothalamus, including the lateral hypothalamic and preoptic areas (18,44). In additio...

Distribution and targets of the relaxin‐3 innervation of the septal area in the rat

“…A consistent ability of RLN3 or RXFP3 agonist peptides to increase food intake in satiated rats has been observed following both icv injection and local injection into several hypothalamic nuclei (McGowan et al, 2005;McGowan et al, 2006;McGowan et al, 2007) ( Kuei et al, 2007); and the effect of RXFP3 activation on feeding is blocked by the intracerebroventricular infusion of the antagonists, R3(B∆23-27)R/I5 (Kuei et al, 2007) and R3(1-23R) (Haugaard-Kedström et al, 2011) suggesting a specific RXFP3-mediated action.…”

Distribution of relaxin‐3 and RXFP3 within arousal, stress, affective, and cognitive circuits of mouse brain

“…In particular, a possible modulation of feeding behavior is predicted in light of the robust increases in food intake and body weight elicited by central infusion of relaxin-3 in rats (McGowan et al, 2005(McGowan et al, , 2006(McGowan et al, , 2007Hida et al, 2006). In line with this, a cohort of mixed background RLN3 KO mice displayed reduced body weight, body fat, and plasma leptin and insulin levels relative to WT controls when fed on a high fat diet ).…”

“…or into hypothalamic nuclei of satiated rats produced an increase in feeding during the first hour postinjection, and local injection into the paraventricular hypothalamic nucleus (PVN) twice a day for 7 days or i.c.v. infusion for 14 days resulted in increased food intake and a sustained body weight gain (McGowan et al, 2005(McGowan et al, , 2006(McGowan et al, , 2007Hida et al, 2006). In contrast to these comprehensive anatomical and initial functional studies in the rat, only limited reports on the murine RLN3/RXFP3 system have appeared.…”

H2 Relaxin Is a Biased Ligand Relative to H3 Relaxin at the Relaxin Family Peptide Receptor 3 (RXFP3)

“…Relaxin-3 expression is up-regulated in response to physical stress in rats by a corticorelin-dependent mechanism (Tanaka et al, 2005), suggesting a role in mediating central stress responses. Relaxin-3 injection into the paraventricular nucleus of the hypothalamus or the fourth ventricle increased food intake in rats (McGowan et al, 2007), also indicating a role in appetite control acting via its cognate receptor, RXFP3. Development of ligands that target RXFP3 would potentially provide drugs for the treatment of obesity and anxiety disorders.…”