Sex-specific effects of relaxin-3 on food intake and body weight gain

Abstract

Relaxin-3 (RLN3) is a neuropeptide that is strongly expressed in the pontine nucleus incertus (NI) and binds with high affinity to its cognate receptor RXFP3. Central administration of RLN3 in rats increases food intake and adiposity. In humans, RLN3 polymorphism has been associated with obesity and hypercholesterolaemia. Emerging evidence suggests that the effects of RLN3 may have sex-specific aspects. Thus, the RLN3 knockout female but not male mice are hypoactive. RLN3 produced stronger orexigenic and obesogenic effects in female rats compared with male rats. In addition, female rats demonstrated higher sensitivity to lower doses of RLN3. Repeated cycles of food restriction and stress were accompanied by an increase in RLN3 expression and hyperphagia in female but not in male rats. Furthermore, stress-induced binge eating in female rats was blocked by an RXFP3 receptor antagonist. RLN3 increased the expression of corticotropin releasing factor in the paraventricular hypothalamic nucleus in male but not in female rats. Conversely, in female rats, RLN3 increased the expression of orexin in the lateral hypothalamus. There is evidence that orexin directly activates the RLN3 neurons in the NI. The positive reinforcement of the RLN3 effects by orexin may intensify behavioural activation and feeding in females. Sex-specific effects of RLN3 may also depend on differential expression of RXFP3 receptors in the brain. Given the higher sensitivity of females to the orexigenic effects of RLN3 and the stress-induced activation of RLN3, the overall data suggest a possible role for RLN3 in eating disorders that show a higher propensity in women.

Linked articles: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.

Figure 1

Cumulative food intake (in mg chow g^‐1 BW) after 30 and 60 min following i.c.v. injections of cerebrospinal fluid (CSF) or 25, 200 and 800 pmol of RLN3 in male (left panel) and female (right panel) rats (n = 9 per group). The micrograph shows an example of a brain section 0.8 mm caudal to the bregma with the guide cannula track (shown by arrow) aimed at the lateral ventricle (LV). *P < 0.05: significantly different compared with CSF‐injected rats of the same sex at the same time point. ^# P < 0.05: significantly different compared with male rats injected with the same dose of RLN3 at the same time point. The line graphs present the results reported in Table 1 in Lenglos et al. (2015).

Figure 2

Twenty‐four‐hour BW gain (in folds to the mean of the respective CSF control group) in male and female (n = 9 per group) rats that received i.c.v. injection of CSF or 25, 200 and 800 pmol of RLN3. *P < 0.05: significantly different compared with the CSF group of the same sex. The bar graphs present the results reported in Table 1 in Lenglos et al. (2015).

Figure 3

Total BW gain (in folds to the mean of the respective CSF control group) in male and female rats (n = 6 per group) injected with i.c.v. CSF or 400 pmol·day⁻¹ of RLN3 for 14 days (reported in Calvez et al., 2015a). *P < 0.05: significantly different compared with the CSF group of the same sex; ^# P < 0.05: significantly different compared with the male rats in the same treatment condition.

Figure 4

The levels of expression of RXFP3 receptor mRNA in the PVN in male and female rats (n = 6) maintained on ad libitum chow in non‐stressful conditions. (A) Optical density (OD) of the hybridization signal of RXFP3 receptor mRNA. Positive hybridization signal of RXFP3 receptor mRNA is shown on the dark‐field micrographs in the PVN in male (B) and female (C) rats. *P < 0.05: significantly different compared with male rats. 3v, third ventricle. Scale bar, 300 μm.

Figure 5

Relative changes induced by i.c.v. administration of RLN3 in the brain and on food intake and BW gain in female rats compared with male rats. The upward and downward arrows show relatively high or low, respectively, effects produced in female rats compared with male rats.