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School of Biomedical Sciences University of Nottingham Medical School Nottingham NG7 2UH United Kingdom, and Faculty of Life Sciences The University of Manchester Manchester M13 9PT United Kingdom
Address all correspondence and requests for reprints to: Francis J. P. Ebling, School of Biomedical Sciences, University of Nottingham Medical School, Queen’s Medical Centre, Nottingham NG7 2UH, United Kingdom. E-mail: fran.ebling{at}nottingham.ac.uk; or Simon M. Luckman, Faculty of Life Sciences, University of Manchester, 1.124 Stopford Building, Oxford Road, Manchester M13 9PT, United Kingdom. E-mail: simon.luckman{at}manchester.ac.uk.
Possibly the most important advance in the last 5 yr in the field of reproductive neuroendocrinology has been the discovery that kisspeptin peptides acting via GPR54 receptors on GnRH neurons are essential for the activation of the hypothalamo-pituitary-gonadal axis at puberty (1, 2). Kisspeptins are members of an extensive and phylogenetically diverse family of peptides (Fig. 1
) that share a common carboxyl-terminal arginine (R) and amidated phenylalanine (F) pair of amino acids, hence the collective term RFamides (3). One RFamide family member has an opposite function to kisspeptin in birds, inhibiting reproductive function by suppressing gonadotropin secretion from the pituitary gland (4), and so has been termed gonadotropin-inhibitory hormone (GnIH, Fig. 1). Increased production of GnIH is important in the seasonal termination of the reproductive period in birds with annual breeding cycles (5). The RFamide-related peptide gene (RFRP) is thought to be the mammalian ortholog of the avian GnIH gene (Fig. 1). This has raised the question of whether the two biologically active peptides derived from this gene (RFRP-1 and RFRP-3) serve a similar function in mammals (6). In this issue, studies in hamsters by Revel and colleagues (7) indicate this is unlikely to be the case, at least as far as the seasonal suppression of reproductive activity is concerned.
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Their main findings were that expression of the RFRP gene and peptide in the hypothalamus decreased markedly in both species of hamsters during the reproductively quiescent phase of the seasonal cycle (7). This is completely at odds with the prediction that would be made if this peptide were to function as an inhibitor of reproductive function, where it would be expected that RFRP should increase before or during short-day-induced inactivation of the reproductive axis. They carried out studies in castrated and testosterone-replaced hamsters that showed that the short-day-induced decrease in RFRP expression is not a consequence of a reduction in the testosterone negative feedback signal (7). Further studies in pinealectomized hamsters confirmed that the reduction of RFRP expression in short days is dependent upon the appropriate nocturnal pattern of melatonin secretion and also confirmed that the reduction in RFRP production occurred at all phases of the circadian cycle (7). These data suggest that melatonin is the main regulator of RFRP expression, and this is consistent with earlier findings in the Syrian hamster that melatonin receptors are present in the same dorsomedial hypothalamic region as RFRP neurons are found in (11).
In many mammalian species, seasonal cycles of reproduction can be viewed as reversible puberty because they result from profound changes in GnRH secretion (12). In the same way that activity of kisspeptin neurons that signal via GPR54 receptors is required for puberty in man and experimental mice, Revel and colleagues (7) have postulated previously that seasonal reactivation of the reproductive axis requires the kisspeptin system to switch on (13). They demonstrated that long-day-induced reproductive function in Syrian hamsters is associated with increased expression of kisspeptin gene in the arcuate nucleus (14) and that chronic intracerebroventricular infusions of kisspeptin-10 can induce testicular recrudescence in hamsters maintained in short days (14). Other researchers have found that reductions in kisspeptin expression also occur in the anteroventral periventricular nucleus in reproductively inactive Siberian hamsters in short days (15, 16). These studies point to a similar role for kisspeptin in pubertal and seasonal activation of reproduction. The current study raises the question of whether or not a reduction in RFRP production might also be necessary for puberty in mammals. Perhaps the observation that expression of the RFRP gene correlates positively with the seasonal degree of reproductive activity is a pointer that puberty will not be a reflection of reduced RFRP production.
Before rejecting completely the notion that RFRP functions as a mammalian GnIH, perhaps it is worth noting that there are some conflicting lines of evidence. First, in several species of rodent, fibers that stain immunopositive with an antiserum raised against the white-crowned sparrow GnIH sequence are in close apposition to GnRH neurons (6). Second, both intracerebroventricular and ip administration of GnIH reduce circulating LH concentrations in Syrian hamsters and rats (6, 17). In view of these lines of evidence, it may well be that RFRP conveys one type of inhibitory signal to the reproductive axis in mammals, perhaps related to steroid negative feedback, but it is not responsible for the profound steroid-independent alterations in GnRH secretion that underlie puberty and seasonal inactivation and reactivation of the reproductive axis (12).
Given the clear photoperiodically regulated changes in hypothalamic RFRP gene expression observed in this study, the question naturally arises as to the function of the products of this gene. The Siberian hamster is not only studied because of its reversible fertility, but is increasingly being used as a model in which to understand the control of energy balance (18). Alongside the seasonal cycle of reproduction is a profound cycle in body weight; hamsters gain weight during long summer photoperiods but then survive winter by reducing foraging and by catabolizing intra-abdominal fat stores (19, 20). As depicted in Fig. 1
, a common feature of many of the RFamide peptides across invertebrate and vertebrate groups is their role in food intake and energy balance (3). In mammals, some are strongly catabolic [e.g. prolactin-releasing peptide (PrRP) and neuropeptide FF (NPFF) Fig. 1], causing a decrease in feeding and/or an increase in energy expenditure (21, 22, 23). The more recently described 43 amino acid pyroglutamylated RFamide peptide (QRFP) has opposing actions (24, 25). The down-regulation of RFRP observed in short days in the current study may indicate that its products exert an anabolic effect in the long-day seasonal mammal. To date, there have been no published data on the action of RFRP peptides on long-term energy balance, although our own unpublished results (Luckman, S. M., in preparation) suggest that neither RFRP-1 or RFRP-3 have significant acute effects on feeding in mice.
Finally, the internuclear location within the hypothalamus of RFRP-containing neurons (7, 9, 10), reminiscent of the dispersed nature of QRFP-containing neurons (25, 26), may be providing a clue as to the possible function of these RFamides. It is noteworthy that other peptides involved in the integration of multiple neuroendocrine functions, e.g. TRH, orexin, cocaine- and amphetamine-regulated transcript, and melanin-concentrating hormone, are also not confined to the classical hypothalamic nuclei. These peptides have important and diverse (though interrelated) actions, including roles in energy homeostasis, reproduction, and arousal. These roles will necessitate their interaction with more than one neuroendocrine axis. It might be that these peptidergic populations form part of a distributed behavioral control column that is activated at critical times of changing body state, for example with puberty or seasonality.
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Footnotes |
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Abbreviations: GnIH, Gonadotropin-inhibitory hormone; NPFF, neuropeptide FF; PrRP, prolactin-releasing peptide; QRFP, 43 amino acid pyroglutamylated RFamide peptide; RFRP, RFamide-related peptide.
The authors’ research programs are supported by the Biotechnology and Biological Sciences Research Council (UK) and The Wellcome Trust.
Disclosure Statement: The authors have nothing to disclose.
Received December 19, 2007.
Accepted for publication December 27, 2007.
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