Evidence that the Type‐2 Gonadotrophin‐Releasing Hormone (GnRH) Receptor Mediates the Behavioural Effects of GnRH‐II on Feeding and Reproduction in Musk Shrews

Abstract

Gonadotrophin-releasing hormone (GnRH) is a regulatory neuropeptide of which there are multiple structural variants. In mammals, a hypothalamic form (GnRH-I) controls gonadotrophin secretion whereas a midbrain form (GnRH-II) appears to have a neuromodulatory role affecting feeding and reproduction. In female musk shrews and mice, central administration of GnRH-II reinstates mating behaviour previously inhibited by food restriction. In addition, GnRH-II treatment also decreases short-term food intake in musk shrews. GnRH-II can bind two different mammalian GnRH receptors (type-1 and type-2), and thus it is unclear which receptor subtype mediates the behavioural effects of this peptide. Adult female musk shrews implanted with i.c.v. cannula were food restricted or fed ad lib and then tested for sexual behaviour or food intake. One hour before testing, animals were pretreated with vehicle or Antide, a potent type-1 GnRH receptor antagonist (at a dose that blocks GnRH-I or -II mediated ovulation). Twenty minutes before testing, females were infused a second time with either GnRH-II or vehicle. Additional females were tested after an infusion of 135-18, a type-1 receptor antagonist that displays agonist actions at the primate type-2 receptor. GnRH-II treatment increased sexual behaviour in underfed female shrews; pretreatment with Antide did not block this action, suggesting that the effects of GnRH-II are not mediated via the type-1 receptor. Similarly, the inhibitory effects of GnRH-II on short-term food intake were not prevented by pretreatment with Antide. The behavioural effects of the type-2 receptor agonist 135-18 were similar to those seen in GnRH-II-treated females, with 135-18 promoting sexual behaviour and decreasing food intake. Collectively, these results indicate that GnRH-II does not act via the type-1 GnRH receptor to regulate mammalian behaviour but likely activates the type-2 GnRH receptor.

Diversity of actions of GnRHs mediated by ligand-induced selective signaling

“…11) [137]. Moreover, an antagonist at the type I GnRH receptor which is an agonist at the type II GnRH receptor (antagonist 135-18 stimulates reproductive behavior in female musk shrews suggesting that the effect is mediated by the type II receptor [60]. This conclusion is further supported by the demonstration that antide which is an antagonist at the type I receptor but is inactive at type II receptors, had no effect on GnRH II stimulation of behavior.…”

“…This conclusion is further supported by the demonstration that antide which is an antagonist at the type I receptor but is inactive at type II receptors, had no effect on GnRH II stimulation of behavior. Interestingly, these effects could only be demonstrated after food restriction and GnRH II itself was found to inhibit feeding behavior in musk shrews [59,60]. Thus, it appears that under normal conditions when animals are satiated the endogenous GnRH II system is fully activating reproductive behavior and exogenous GnRH II is not required.…”

Caloric restriction: Impact upon pituitary function and reproduction

“…decline of circulating LH and testosterone, however can be reversed rapidly upon feeding, suggesting that there is a calorie-dependent regulation of GnRH pulse-generator output (Aloi et al, 1997). Further linking GnRH function, there is evidence of not only GnRHs role in generic neuronal excitability during fasting (Röjdmark, 1987), controlling the desire behind food intake (Kauffman et al, 2005a), but there is also evidence that food intake itself directly controls the mRNA and protein levels of GnRH in mammalian brains (Kauffman et al, 2006). It has been shown that even short periods of dietary energy deprivation (24-72 h) can have dramatic effects upon the hypothalamic-pituitary-gonadal (HPG) axis in humans and animal models.…”

Neuropeptide Y influences acute food intake and energy status affects NPY immunoreactivity in the female musk shrew (Suncus murinus)

“…In contrast, when females are on ad libitum diets or they are food restricted, acute infusions of GnRH II depressed food intake (Kauffman, Wills, Millar, and Rissman, 2005). Since GnRH II is an evolutionarily conserved neuropeptide found in various vertebrates and non-vertebrate species, it is possible that it interacts with some of the other highly conserved hypothalamic peptides that modulate feeding behavior; such as NPY.…”