Abstract
Reproduction in mammals is an extremely energy-intensive process and is therefore tightly controlled by the body's energy status. Changes in the nutritional status of the body cause fluctuations in the levels of peripheral metabolic hormone signals, such as leptin, insulin, and ghrelin, which provide feedback to the hypothalamus and integrate to coordinate metabolism and fertility. Therefore, to link energy and reproduction, energetic information must be centrally transmitted to gonadotropin-releasing hormone (GnRH) neurons that act as reproductive gating. However, GnRH neurons themselves are rarely directly involved in energy information perception. First, as key factors in the control of GnRH neurons, we describe the direct role of Kisspeptin and Arg-Phe amide-related peptide-3 (RFRP-3) neurons in mediating metabolic signaling. Second, we focused on summarizing the roles of metabolic hormone-sensitive neurons in mediating peripheral energy hormone signaling. Some of these hormone-sensitive neurons can directly transmit energy information to GnRH neurons, such as Orexin neurons, while others act indirectly through other neurons such as Kisspeptin, RFRP-3 neuron, and (pituitary adenylate cyclase-activating polypeptide) PACAP neurons. In addition, as another important aspect of the integration of metabolism and reproduction, the impact of reproductive signaling itself on metabolic function was also considered, as exemplified by our examination of the role of Kisspeptin and RFRP-3 in feeding control. This review summarizes the latest research progress in related fields, in order to more fully understand the central neuropeptide network that integrates energy metabolism and reproduction.
Introduction
In mammals, the close link between energy metabolism and reproduction has been well explained (Schneider 2004). Due to the high energy consumption of reproduction, it is strictly regulated by energy metabolism factors (Manfredi-Lozano et al. 2018, Navarro 2020). For example, in the case of negative energy balance in which fasting leads to energy/nutrient deficiency, the onset of puberty and the acquisition of fertility are often delayed or inhibited to ensure the survival of the individual as a priority. In turn, reproduction is one of the most important physiological behaviors of organisms, and the activation of reproduction-related regulators also affects the metabolic function and energy homeostasis of the body, such as body weight, energy expenditure, and feeding (Moriwaki et al. 2020, Hudson & Kauffman 2022); however, the neuroendocrine basis connecting these two parts in mammals remains largely unknown.
Reproduction is coordinated by the hypothalamic–pituitary–gonadal (HPG) axis in mammals. GnRH is produced by the neurosecretory cells of the hypothalamic preoptic area (POA) and is released in the median eminence (ME), where it regulates the synthesis and release of gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) from the anterior pituitary. The gonadotropins act on the gonads to stimulate gonadal development through the secretion of sex steroid hormones. These steroids, in turn, provide feedback to the brain to complete the HPG axis and regulate the reproductive cycle. Thus, hypothalamic gonadotropin-releasing hormone (GnRH) is considered as the key player in the regulation of reproduction in mammals (Evans & Anderson 2017, Zhao et al. 2021).
To integrate metabolic and reproductive functions, information about the energy status of the organism must be centrally transmitted to GnRH neurons. Due to the lack of key metabolic hormone receptors such as leptin and insulin in GnRH neurons, searching for the integration elements as ‘middlemen’ and their mediating central neuroendocrine pathways has been a research hotspot in this field. Existing studies suggest that Kisspeptin and RFRP-3 neurons function as key integrators coordinating energy metabolism and reproduction. With the development of research, it has been found that Kisspeptin and RFRP-3 neurons are not the main peripheral hormone mediators connecting the metabolic control of GnRH neurons despite being the key regulators of GnRH neurons although they may mediate part of the metabolic hormone effects (Manfredi-Lozano et al. 2018). Therefore, some metabolic hormone-sensitive neurons and their major neuropeptide products, such as pro-opiomelanocortin (POMC)/cocaine and amphetamine-regulated transcript (CART), agouti-related peptide (AgRP)/neuropeptide Y (NPY), γ-amino-butyric acid (GABA), nitric oxide (NO), orexin, galanin-like peptide (GALP), and pituitary adenylate cyclase-activating polypeptide (PACAP), have attracted our attention. These neurons are under the control of metabolic hormones and control kisspeptin, RFRP-3, and GnRH neurons; therefore, these neurons are involved in the transmission of nutritional information to threproductive neurons. In addition, as an important aspect of the interaction between metabolism and reproduction, the control of energy metabolism through reproductive signals is also worthy of attention (Ronnekleiv et al. 2022, Singh et al. 2022). In recent years, continuous studies have reported the metabolic effects of Kisspeptin and RFRP-3 in addition to their reproductive effects. In this paper, the central neuropeptides related to energy and reproduction in the hypothalamus and their possible pathways with GnRH neurons are described, and the increasingly prominent metabolic effects of reproductive neuropeptides are summarized in order to expand our understanding of the integration mechanism of energy and reproduction and provide new tools and targets for better prevention and management of animal reproduction in practice.
Peripheral metabolic hormones linking energy/nutritional status and fertility
The continuation of the species depends on successful reproduction. As mentioned earlier, due to the high-energy demands of reproduction, the reproductive control core of the brain, GnRH neurons, must receive signals about nutritional status to determine whether the organism is currently in the optimal conditions for successful reproduction. One of the signals of nutritional status is the adipose-derived hormone leptin. Circulating leptin concentrations decrease rapidly with fasting (Vazquez et al. 2015) and are positively correlated with body adiposity, thereby conveying information about body energy status and long-term energy stores to the brain. Low leptin levels generally reflect low fat and energy deficiency and are associated with the reproductive suppression (Ruscica et al. 2016). Thus, leptin is considered a key permissive signal for metabolic control of fertility. Paradoxically, conditions with excess leptin (such as morbid obesity) also affect puberty and reproductive capacity (Roa & Tena-Sempere 2014). Although some progress has been made, such as the idea that inflammatory factors play an important role (Chen et al. 2022), the actual role and underlying mechanisms of leptin in this situation still need to be further explored.
In addition, many common peripheral metabolic hormones are closely related to reproduction. For instance, insulin, a pancreatic hormone that regulates glucose homeostasis and body weight, also stimulates the reproductive axis, as conditions of insulin deficiency are often associated with gonadotropin suppression and reproductive defects (Pralong 2010). Studies in rodents and female mammals have shown that elevated peripheral insulin levels significantly increase GnRH/LH secretion (Burcelin et al. 2003, Moret et al. 2009). In addition, mice deficient in brain-specific insulin receptor (IR) showed significant gonadal function decline due to reduced GnRH secretion (Bruning et al. 2000), indicating the positive effect of insulin in promoting GnRH/LH secretion. In addition, clinical studies have shown that diabetic insulin insufficiency is associated with hypothalamic hypogonadism and that energy-deficient hypothalamic amenorrhea women have reduced insulin levels, further suggesting the critical stimulatory role of insulin in the HPG axis (Evans et al. 2021).
Ghrelin, derived from the gut, is also a prototypical peripheral hormone involved in the control of reproductive metabolism by acting through its receptor, growth hormone secretagogue receptor (GHSR), expressed in hypothalamic neurons in the arcuate (ARC) (Andrews 2011). Indeed, the negative energy balance translates into an increase in circulating ghrelin levels (Martins et al. 2016). A chronic increase in circulating ghrelin levels has been observed in chronically malnourished women and is associated with suppression of reproductive function (Scheid & De Souza 2010). In the male reproductive system, it has been reported that intestinal hormones may cooperate with other regulatory signals to control energy homeostasis and reproduction (Alves et al. 2016). Unlike leptin and insulin, ghrelin exhibits inhibition of GnRH/LH release and reproductive function (Furuta et al. 2001a, Kluge et al. 2013). Hypothalamic ghrelin administration impairs spermatogenesis in mice by inhibiting the HPG axis, thereby inhibiting reproductive function (Poretti et al. 2018). Preclinical studies reported a delayed effect of ghrelin on puberty initiation and noted the inhibition of LH secretion in vivo by ghrelin (Martini et al. 2006). Moreover, experimental evidence from a variety of mammals such as ovarectomized rats (Furuta et al. 2001b), sheep (Iqbal et al. 2006), monkeys (Vulliémoz et al. 2004), and humans (Kluge et al. 2007, Lanfranco et al. 2008) also confirmed that ghrelin significantly reduced the frequency of LH pulse release and exhibited varying degrees of impaired reproductive function. In good agreement, GnRH secretion was significantly inhibited by ghrelin (Fernández-Fernández et al. 2005), and in a study using the GT1-7 cell line (immortalized GnRH cells), Ca2+-imaging revealed a ghrelin-triggered increase of the Ca2+-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHSR-antagonist JMV2959 (10 µM) suggesting direct action of ghrelin to GnRH neurons (Farkas et al. 2013). These studies all provide ample evidence for the central inhibitory effect of ghrelin on reproduction. In addition, ghrelin inhibits the mRNA transcription of Kiss1 and its receptor GPR54, a G-protein-coupled receptor with a conserved sequence in a transmembrane structure (de Roux et al. 2003, Sagheb et al. 2017). Research confirms that intravenous administration of ghrelin can downregulate the expression of Kiss1 mRNA in female rats in the POA area, thereby indirectly inhibiting the frequency of LH pulse and delaying the onset of puberty (Forbes et al. 2009). Given the critical role of Kisspeptin signaling in HPG axis activation (as discussed later), the ability of ghrelin to downregulate Kiss1 expression in the POA may be an important regulatory pathway in the Ghrelin-related inhibition of pulsatile LH secretion. These lines of evidence strongly suggest that ghrelin plays a key role in the mechanism by which low-energy supply inhibits the neuroendocrine reproductive axis.
As discussed above, these hormones control fertility in a way that reflects the energy status of the individual, linking energy metabolism and reproduction; however, the neural circuitry by which they affect GnRH neurons remains largely unknown. Due to the lack of leptin receptor (LEPR), GnRH neurons are not directly regulated by leptin (Quennell et al. 2009). Selective excision of IR in GnRH neurons did not disrupt the timing of puberty or abolish reproductive function in male or female mice (DiVall et al. 2010), in contrast to the strong gonadotropin phenotype exhibited by excision of insulin receptor neurons (Bruning et al. 2000), which suggests that normal fertility requires the expression of IR in the brain but not GnRH-specific IR, indicating that the effect of insulin on GnRH secretion is mainly mediated indirectly. Although there is evidence that Ghrelin can regulate GnRH neurons directly (Farkas et al. 2013), many of its neuroendocrine effects appear to be mediated by hypothalamic afferent GnRH neuronal circuits (Schaeffer et al. 2013, Smith et al. 2013, Evans et al. 2014). The possible mode of action of ghrelin in inhibiting hypothalamic GnRH/LH secretion includes the possible synergistic effect of neuropeptide Y, kisspeptin, and gonadotropin-inhibitory hormone (GnIH) (Vulliemoz et al. 2008, Forbes et al. 2009, Celik et al. 2016). Taken together, these findings suggest that leptin, insulin, and ghrelin, as classical examples of metabolic signals controlling central elements of the HPG axis, indirectly regulate the secretory activity of GnRH neurons by modulating key neuropeptide pathways and neuronal inputs. That is, neuroendocrine integration of reproductive trophic signals mainly occurs upstream of GnRH neurons (Evans & Anderson 2017).
Role of key regulators of GnRH release in the metabolic control of fertility
As the predominantly indirect mode of action of peripheral nutritional factors on GnRH neurons has been demonstrated, the search for a putative intermediate pathway linking metabolism and reproduction has become a focus of attention. These mediators integrate metabolic signals upstream of GnRH neurons, and GnRH acts as the final output of this regulatory signaling function to regulate fertility. Kisspeptin and GnIH (RFRP-3 in mammals) have been shown to play a key role in regulating GnRH synthesis and release, which stimulate and inhibit mostly GnRH neurons, respectively (Tsutsui et al. 2000, de Roux et al. 2003). As the most likely candidate factor mediating reproductive metabolic control, since their role at the reproductive level has been determined, their regulation through metabolic signals has become the focus of attention (Castellano & Tena-Sempere 2016).
Stimulation and metabolic control of GnRH neurons by Kisspeptin
Kisspeptin (encoded by the Kiss1 gene) and its receptor Kiss1r (aka GPR54) have been identified as a potent stimulator of GnRH in a variety of mammals including humans (Pinilla et al. 2012, Nagae et al. 2021), through acting directly on GnRH neurons. In mammals, Kiss1 neurons are mainly found in the hypothalamic arcuate nucleus (ARC) and the anteroventral periventricular zone around the third ventricle (AVPV) or in the POA of non-rodent mammals (Yeo et al. 2016), where females usually have more Kiss1AVPV neurons than males (Semaan & Kauffman 2010). Kiss1AVPV neurons play an important role in the preovulatory LH surge in females. In contrast, Kiss1ARC neurons predominantly co-express the neuropeptides neurokinin B (NKB) and dynorphin (Dyn), collectively known as KNDy neurons, and are the major regulators of GnRH/LH pulse release (Tsukamura 2022).
It should be emphasized that functional LEPR expression is low or absent in Kiss1 neurons (Cravo et al. 2011, Louis et al. 2011), so the role of Kisspeptin in mediating the effects of leptin on GnRH neurons is limited (Luo et al. 2016, Ronnekleiv et al. 2019). Moreover, mouse hypothalamic Kiss1 neuron-specific LEPR knockout (KO) had no effect on puberty and reproductive function (Donato et al. 2011), and re-expression of endogenous LEPR in Kiss1 neurons was not sufficient to improve reproductive function in female db/db mice (Cravo et al. 2013). These results all point out that direct leptin signaling mediated by Kiss1 neurons is not essential for the reproduction and requires the involvement of other leptin-sensitive neurons (Chen et al. 2022). Interestingly, LEPR are not physiologically expressed in the central nervous system of ob/ob mice, but central administration of leptin to adolescent female mice decreased Kiss1, GnRH, and LH expression after 4 h (Ahn et al. 2012). This implies that even in the absence of LEPR, leptin can still bind to the Kiss1/GPR54 system through compensatory action, thereby regulating GnRH/LH secretion. In addition to leptin, IR expression has been detected in mouse Kiss1 neurons (Campbell et al. 2017), and male and female mice lacking IR in Kiss1 neurons exhibit delayed sexual maturation or decreased LH secretion (Qiu et al. 2013). Alternatively, the insulin/IR system appears to directly activate Kiss1 neurons via canonical transient receptor potential 5 channel (TRPC5) (Qiu et al. 2014). Additional studies have reported that the loss of IR in Kiss1 neurons does not alter LH levels in adult lean mice (Qiu et al. 2015). This finding seems to indicate that insulin signaling mediated by Kiss1 neurons in the hypothalamus plays an important role only during pubertal development. Moreover, while another study using double-labeled immunohistochemistry found that IR was detected in only approximately 5% of Kisspeptin immunoreactive cells, male and female Kiss1 neuron-specific IR KO mice showed no delay in the onset of puberty and were fully fertile (Evans et al. 2014, 2021). These findings contradict previous ones, as they suggest that insulin signaling via Kiss1 neurons does not appear to be essential for reproduction. Since the findings are inconsistent, the insulin effects mediated by Kiss1 neurons need more investigation. In addition, Kiss1ARC neurons may receive ghrelin input directly but not Kiss1AVPV/POA neurons (Andrews 2011, De Bond & Smith 2014, Conde & Roepke 2020).
Inhibition and metabolic control of GnRH neurons by RFRP-3
GnIH/RFamide-related peptides (RFRPs) are a key class of GnRH inhibitors (Hu et al. 2019), of which RFRP-3 is considered to be the true homolog of GnIH in mammalian gonadotropin secretion (Henningsen et al. 2017). RFRP-3 is a hypothalamic dodecapeptide, which is synthesized and secreted by the dorsomedial hypothalamus (DMH) of mammals (Kriegsfeld et al. 2006, Legagneux et al. 2009). RFRP-3 inhibits reproductive/gonadal function by regulating GnRH-mediated gonadotropin release through its receptor G-protein-coupled receptor 147 (GPR147) (Tsutsui et al. 2010). In vitro experiments have shown that RFRP-3 directly reduces the firing rate of GnRH neurons in hypothalamic brain slices by inhibiting the hyperpolarization of glutamatergic GnRH neurons mediated by K+ channels (Ducret et al. 2009, Wu et al. 2009b). Projections of RFRP-3 neurons found in the POA are close to GnRH neurons containing GPR147 (Ukena et al. 2003). This suggests that RFRP-3 released into ME can act directly on GnRH neurons to inhibit their secretory activity. Furthermore, in mice, about 12% of Kiss1AVPV/POA neurons and about 25% of Kiss1ARC neurons contain GPR147 (Poling et al. 2017), and a study confirmed that RFRP-3 can inhibit the expression of Kisspeptin in the hypothalamus when administered in the ventricle (Han et al. 2017). Additional studies have suggested that RFRP-3 may regulate Kiss1ARC neurons in mice, although it is unlikely that Kiss1 neurons have any direct interaction with RFRP-3 neurons (Poling et al. 2012).
Regarding RFRP-3 neuron-mediated metabolic control, earlier studies have shown that leptin has little or no effect on RFRP-3 neurons, and it is unlikely to be an important neuronal pathway for leptin's metabolic regulation of fertility (Evans et al. 2014). The regulation of RFRP-3 neurons by leptin may be mainly through indirect signaling (at least in adult mice) (Poling et al. 2014). However, subsequent studies have shown that 15%-20% of RFRP-3 neurons express LEPRs and that leptin can activate intracellular calcium signaling in RFRP-3 neurons through a protein kinase C(PKC)-dependent pathway, suggesting that leptin may act on GnRH neurons through RFRP-3 cells (Ozcan et al. 2015). Clearly, evidence on whether RFRP-3 mediates metabolic control is scarce, and more studies are needed to elucidate the direct effects of metabolic hormones on RFRP-3.
Hypothalamic neural network for metabolic control of reproduction neurons
As discussed above, Kiss1 and RFRP-3 neurons and their secreted products, which are key factors in the regulation of GNRH neurons, do not appear to be the primary targets of peripheral energy homeostasis regulatory hormones although they may mediate some of the effects. Therefore, it is necessary to focus on the interactions between metabolic hormone-sensitive neurons involved in energy homeostasis and reproductive neurons (Kiss1 neurons, RFRP-3 neurons, and GnRH neurons) to elucidate the central neuropeptide network that links metabolic and nutritional status to reproduction. In this part, we have made the corresponding summary as follows (Fig. 1).
Schematic representation of hypothalamic neuroendocrine pathways in the control of reproductive metabolism in mammals. GnRH neurons, as reproductive gating, receive modulatory input directly or indirectly from a wide range of regulatory signals and pathways, involving a variety of neuropeptides and neurotransmitters. As key upstream regulatory elements of GnRH neurons, Kisspeptin and RFRP-3 neurons play an important role in integrating the entire neural network. In addition, multiple metabolic hormone-sensitive neurons were involved, including POMC/CART, AgRP/NPY, GABA, PACAP, nNOS, orexin, GAL, MCH, GALP, and NMS neurons. GABA, γ-amino-butyric acid; GAL, Galanin; GALP, galanin-like peptide; MCH, melanin-concentrating hormone; NMS, Neuromedin S; nNOS neuronal nitric oxide synthase; PACAP, pituitary adenylate cyclase-activating polypeptide; POMC/CART, pro-opiomelanocortin/cocaine and amphetamine-regulated transcript
Citation: Journal of Endocrinology 258, 3; 10.1530/JOE-23-0079
Potential neuroendocrine pathways that transmit metabolic signals to Kiss1 neurons
POMC/CART neurons located in the ARC are involved in the transmission of leptin effects to reproductive neurons (Timper & Bruning 2017). Peripheral leptin levels can directly stimulate POMC neurons, and LEPRs deficient in POMC neurons exhibit reproductive dysfunction in mice (Mizuno et al. 1998, Vrang et al. 2002, Hill et al. 2010). This provides evidence for POMCARC neurons as a hub connecting energy state and reproduction. Later studies confirmed that the main product of POMC neurons, α-MSH (a melanocortin), transmits the permissive effect of leptin on the onset of puberty through Kiss1ARC neurons (Manfredi-Lozano et al. 2016). Another major product, CART, can also stimulate Kiss1 neurons located in the AVPV and ARC. Alternatively, CART reduces its expression when energy is insufficient and contributes to the inhibition of the HPG axis (True et al. 2013), and the existence of this multipathway regulation may be required for the refined regulation of reproduction. Unlike leptin, evidence from mice suggests that insulin signaling via POMC/CART neurons located in the ARC does not appear to be required, as specific IR KO in POMCARC neurons does not affect fertility (Konner et al. 2007). As we mentioned in section ’Peripheral metabolic hormones linking energy/nutritional status and fertility‘, given the critical stimulatory effect of insulin on the HPG axis, more studies are needed to find mediators that play a role in insulin signaling.
Correspondingly, AgRP/NPY neurons are also involved in the mediating pathway of hypothalamic transmission of leptin effects (Timper & Bruning 2017). AgRP/NPY neurons express LEPR and are negatively regulated by leptin (McShane et al. 1992, Sato et al. 2005, Vulliemoz et al. 2005, Roa & Herbison 2012). In ob/ob female mice, elimination of AgRP-expressing neurons restored metabolic and reproductive function (Wu et al. 2012). Disruption of NPY signaling by deletion of the NPY receptor, Y2R, alleviated infertility in ob/ob mice (Manfredi-Lozano et al. 2016). These studies provide direct evidence that AgRP neurons are involved in mediating energy metabolism and reproduction. In addition, Kiss1 neurons may mediate the effects of AgRP/NPY neurons on the HPG axis. It has been shown that AgRP neurons project to Kiss1 neurons located in AVPV and ARC while inhibiting their activity (Atala 2018, Merkley et al. 2021). Another study pointed to the direct inhibition of Kiss1ARC neurons by NPY via NPY receptor Y1R in male and female mice (Hessler et al. 2020). Given the antagonistic roles of NPY/AgRP neurons and POMC/CART neurons in mediating leptin effects, it is clear that the interaction of these neuronal populations contributes to the ultimate effects of leptin on Kiss1 neurons. For example, AgRP can function as an endogenous antagonist of melanocortin receptor 3/4 (MC3/4R) (Ollmann et al. 1997). In addition to leptin, ghrelin can stimulate AgRP/NPY neurons and inhibit POMC/CART neurons through its receptor GHSR (Lebrethon et al. 2007, Chen et al. 2017). Interestingly, there appears to be a non-GHSR-dependent pathway that allows ghrelin to stimulate POMC neurons (Chen et al. 2017).
GABA, the major inhibitory neurotransmitter in the mammalian central nervous system, has been identified as a key player in the regulation of reproduction by leptin. In a mouse model of LEPR deficiency in GABAergic neurons, Kiss1 neuron expression is reduced and leads to delayed puberty and decreased fertility (Martin et al. 2014). GABA acts through two receptors, the GABAA receptor (GABAAR) and the GABAB receptor (GABABR). GABA has been found to act on GABAAR on Kiss1 neurons, at least in monkeys and humans (Di Giorgio et al. 2019). In addition, NPY/AgRP neurons also co-express GABA. Thus, the reproductive phenotype of the LEPR-deficient mouse model of GABAergic neurons described above may result in part from the elimination and/or reduction of leptin inhibition of NPY/AgRP neurons (Evans & Anderson 2017). Indeed, GABA co-expression mediated by leptin signaling has been shown to be sufficient to maintain fertility in NPY/AgRP neurons (Egan et al. 2017, Marshall et al. 2017).
PACAP neurons located in the PMV may contribute to the transmission of leptin effects to reproductive neurons. First, the loss of LEPR in PACAP neurons results in mouse infertility (Ross et al. 2018). Second, additional data support that PACAP neurons influence the kisspeptin–GnRH neuronal network by modulating Kiss1ARC neurons, thereby affecting fertility (Barabas et al. 2022). These data support a role for PACAP neurons in mediating the indirect pattern of leptin on reproductive neurons.
Because of their critical importance, in this section, we first focus on the possible role of POMC/CART and NPY/AgRP neurons, two major neuronal populations located in the ARC, in transmitting metabolic signals to control puberty and fertility. The direct effects (stimulation or inhibition) of POMC/CART and NPY/AgRP neurons and their major products on the presence of Kiss1ARC neurons located in the ARC are shown in Fig. 1. It can be clearly understood that the POMC/CART and NPY/AgRP neuronal populations play an important mediator role in the transmission of leptin signaling to kissspeptin neurons, which in turn affect GnRH neurons as reproductive gating. In addition, increasing evidence suggests that GABAergic neurons and populations of PACAP neurons are important first-order targets of peripheral metabolic signals (a typical example is leptin) that mediate the transmission of metabolic signals to Kiss1ARC neurons. The property possessed by the above-mentioned neuronal populations to transmit metabolic hormone signals to downstream reproductive neurons makes them ideal integrators for the combined control of metabolic and reproductive functions.
Potential neuroendocrine pathways that transmit metabolic signals to GnRH neurons
The transmission of metabolic signals to GnRH neurons via Kiss1 neurons is critical for the control of reproductive metabolism. However, due to the complexity and redundancy of the hypothalamic GnRH neuronal network, it can be speculated that there must be hormone-sensitive neuron-GnRH neuronal pathways of hormone metabolism independent of Kiss1 neurons to implement finer regulation of reproductive metabolic control processes. For example, POMC/CART, NPY/AgRP neurons, in addition to transmitting metabolic information via Kiss1 neurons, can also directly regulate the secretory activity of GnRH neurons, and in this section we will focus on their direct effects on GnRH. Therefore, those neurons that respond positively to metabolic hormones and that have a direct effect on GnRH neurons are the focus of the review in this section. In addition to the POMC/CART and NPY/AgRP neurons mentioned above, galanin (GAL) and GALP neurons located mainly in ARC, neuronal nitric oxide synthase (nNOS) neurons in AVPV/POA, and Orexin and melanin-concentrating hormone (MCH) neurons located in LHA are also our next focus, which also play an important role in the transmission of metabolic hormones (e.g. leptin) to GnRH neurons, and Fig. 1 shows the distribution of these neurons and their direct effects on GnRH neurons. It is not difficult to understand that it is precisely because of the simultaneous involvement of multiple neuronal populations that the precise control of reproduction by energy is achieved, which is clearly of great importance.
α-MSH and CART secreted by POMC/CART neurons can also directly regulate GnRH neuronal secretory activity through MC3/4R (Manfredi-Lozano et al. 2018). CART has been shown to stimulate GnRH neurons in mice (True et al. 2013). These studies provide convincing evidence for the involvement of NPY/AgRP neurons in direct modulatory effects on GnRH neurons. In addition, NPY/AgRP neurons have been shown to project to GnRH nuclei and nerve endings, and NPY and AgRP inhibit GnRH/LH secretion in a variety of species and conditions (Estrada et al. 2003, Vulliemoz et al. 2005). Furthermore, a direct effect of GABA on GnRH neurons was also found. Liu et al. suggest that in the vast majority of GnRH neurons, there is a novel dendritic region called the distal dendrite, which is regulated by GABAergic inputs in a sexual and estrous cycle-dependent manner, with GABABR-mediated inhibition as its major signaling mode. This provides a novel kisspeptin-independent pathway for the regulation of pulse and spike patterns of GnRH secretion in rodents, implying a unique role for GABAergic neurons in the metabolic control of fertility (Liu et al. 2022).
NO is a gaseous neurotransmitter synthesized by neuronal nitric oxide synthase (nNOS) neurons located in POA, which is believed to play an important role in mediating the transmission of leptin signals to the HPG axis (Bellefontaine et al. 2014, Constantin et al. 2021). In mice, nNOS neuron-specific LEPR KO resulted in phagocytic obesity, reduced energy expenditure, and significant hyperglycemia close to that of db/db mice, suggesting that LEPR-expressing nNOS neurons are essential for leptin control of energy metabolism (Leshan et al. 2012). Moreover, emerging evidence from humans and mice further emphasizes the important role of NO in reproduction. In clinical studies, a timely lack of nNOS activity creates GnRH deficiency, and all patients therefore present absent puberty. Animal experiments have reached consistent conclusions and confirmed that NO treatment during a critical window period can reverse the sexual maturation defects caused by the lack of nNOS activity (Chachlaki et al. 2022). In fact, NO can act directly on GnRH neurons, which is thought to be key to the preovulation surge of GnRH (Prashar et al. 2021). In addition, studies have shown that Kiss1ARC neuron-mediated nNOS activation is an important event of GnRH neuronal activation, revealing the existence and importance of the Kisspeptin–nNOS–GnRH pathway (Prashar et al. 2021). Further, nNOS neurons express Kiss1r. Considering that nNOS neurons mediate leptin effect, it can be assumed that the leptin–nNOS–Kisspeptin–GnRH pathway exists, and more studies are needed to further evaluate the role between them. Interestingly, subsets of nNOS neurons co-express GABA (Marshall et al. 2017) and glutamate (Lin et al. 2004) and may also be one of these neurotransmitters mediating the downstream metabolic effects of leptin.
Orexin neurons located in the lateral hypothalamic area (LHA) mediate the regulation of leptin and ghrelin (Yamanaka et al. 2003, Burdakov et al. 2005, Kirsz et al. 2017) and provide partial direct input to GnRH neurons (Skrapits et al. 2015). Studies have shown that orexin can directly regulate GnRH cells and inhibit GnRH gene expression (Sasson et al. 2006, Gaskins & Moenter 2012). In addition, orexin decreased the relative expression of Kiss1 and NKB genes and increased the relative expression of Dyn genes, suggesting that the effects of OXA on the reproductive system and GnRH occur, at least in part, by affecting KNDy neurons in upstream of GnRH neurons (Hosseini & Khazali 2018).
Galanin (GAL) is a 29-amino acid small neuropeptide that is highly conserved among species (Rökaeus et al. 1998) and mainly mediates its action through the subtype receptor galanin receptor-1 (GAL-R1) (Jungnickel & Gundlach 2005). GAL neurons are widely distributed in the peripheral and central nervous systems of mammals (Jacobowitz et al. 2004) in regions such as ARC and are considered important intermediates of HPG axis signaling and are involved in the control of many physiological functions, including feeding regulation (Baranowska et al. 2003) and neuroendocrine regulation of reproduction (Gabriel et al. 1993, Grafstein-Dunn et al. 1994). In sheep, the co-localization of GAL-R1 expression and GnRH was found (Dufourny & Skinner 2005), suggesting that GAL directly affects at least one subpopulation of GnRH neurons through GAL-R1 receptors. Studies in rats have shown that GAL is a target of hypothalamic leptin signaling (Sahu 1998a ) and has been shown to stimulate hypothalamic GnRH/LH secretion (Lopez & Negro-Vilar 1990, Lopez et al. 1991). Unfortunately, the fertility of these animals has not been directly assessed. In addition, GAL may be released together with Kisspeptin from the axon subset of Kiss1 neurons to GnRH neurons, where both the GAL-R1 and GAL-R2 isoforms of the GAL receptor appear to be expressed (Constantin & Wray 2016). These lines of evidence all suggest that GAL may also be an important link between energy metabolism and reproductive circuits.
MCH is a small cyclic peptide of 19 amino acids that mediates its function through two receptors, MCHR 1 and MCHR 2, of which only MCHR 1 is shared by all mammals (Al-Massadi et al. 2021). In mammals, MCH-producing neurons are specifically located in the LHA and zona incerta and have extensive neuronal projections throughout the brain (Bittencourt et al. 1992, Bittencourt 2011). MCH has been shown to exert a direct postsynaptic inhibitory effect on GnRH neurons, mediated by a postsynaptic mechanism transduced by MCHR 1 that involves the opening of Ba2+-sensitive K+ channels (Williamson-Hughes et al. 2005, Wu et al. 2009a). Alternatively, inhibition of MCH interrupts or blocks the sustained excitatory action of hypothalamic Kiss1 neurons (Wu et al. 2009a), and Kisspeptin is required for the reproduction. In addition, modulation of postsynaptic effects by MCH appears to be one of the mechanisms involved in leptin signaling (Sahu 1998a,b), suggesting that MCH may also function as an important mediator of metabolic control of fertility.
GALP-expressing neurons located in ARC are believed to play an important role in the metabolic control of fertility (Celik et al. 2015, Shioda et al. 2011). These neuronal populations are regulated by leptin and insulin and can directly regulate GnRH neurons (Jureus et al. 2000, Takatsu et al. 2001, Cunningham et al. 2002), thereby linking the body’s nutrient reserves to fertility (Takenoya et al. 2006). In addition, Kiss1ARC neurons may also be involved in mediating the regulation of GALP on GnRH neurons to promote pubertal development (Mohr et al. 2012).
Potential neuroendocrine pathways that transmit metabolic signals to RFRP-3 neurons
RFRP-3 neurons have been reported to interact with POMC/CART and AgRP/NPY neurons, but critical experimental evidence is lacking on whether these neuronal populations are involved in mediating metabolic control of RFRP-3 by metabolic hormones (Crown et al. 2007, Anjum et al. 2021). Despite many doubts, a number of recent studies suggest that POMC/NPY neurons, as a downstream target of RFRP-3, play an important role in food intake and energy homeostasis (as discussed later) (Singh et al. 2022). In addition, RFRP-3 neurons also express the orexin receptor (OXR) (Singh et al. 2022). Recent studies from intracerebroventricular (ICV) injection showed that orexin A decreased the relative expression of the GnRH gene while increasing the relative expression of RFRP-3 and GPR147 genes. This seems to imply that orexin regulation of the HPG axis occurs, at least in part, by affecting the RFRP-3/GPR147 system upstream of GnRH neurons (Hefshejanni & Khazali 2019), but further studies are needed.
Other neuronal populations
Although the aforementioned neuronal populations are arguably the key populations involved in mediating the transmission of hormonal signals to reproductive neurons, there is also evidence supporting the involvement of others. For example, Neuromedin S (NMS) is a 36-amino acid polypeptide mainly distributed in the suprachiasmatic nucleus (SCN) and also expressed in the paraventricular nucleus of the hypothalamus (PVH) and ARC (Fujii et al. 2000, Howard et al. 2000, Kojima et al. 2000, Raddatz et al. 2000, Mori et al. 2005). NMS has two receptors, NMS receptor 1 (NMU1R) and NMS receptor 2 (NMU2R). NMU1R is mainly expressed in peripheral tissues and organs, such as the gastrointestinal tract, while NMU2R is mainly expressed in the central nervous system, such as PVH and the arcuate nucleus (Shan et al. 2000, Brighton et al. 2004, Chen et al. 2006). Recent studies have proposed NMS as a downstream effector of leptin (Vigo et al. 2007), mediating the positive regulation of leptin on the reproductive axis in female animals (Casanueva & Dieguez 1999, Cunningham et al. 1999). Vigo et al. found that lateral ventricular injection of NMS can upregulate the expression of the POMC gene in the hypothalamic ARC of animals (Miyazato et al. 2008). It is suggested that NMS may indirectly participate in the regulation of animal feeding and reproductive activities by affecting the activity of the POMC neurons in the hypothalamic ARC (Kriegsfeld et al. 2006). Given that NMS are central downstream effectors of leptin and that NMS similarly induce POMC mRNA expression in the hypothalamic ARC of animals, it is clear that NMS may act as a bridge between energy metabolism and reproductive stages. Although NMS may regulate the HPG axis at the central level by promoting GnRH release and subsequent LH release, it is not known whether NMS affects the activity of GnRH neurons and whether they are dependent on Kiss1 neurons. More experimental evidence is needed to clarify the relevant content. Substance P (SP) and neurokinin A (NKA), encoded by the Tac1 gene, are members of the tachykinin family (Ogawa et al. 2021). In mammals, the SP/NK1R and NKA/NK2R systems have been shown to be effective in regulating GnRH and LH secretion, and they may work together with NKB/NK3R. It controls GnRH release, at least in part, by acting on Kiss1 neurons (Maguire et al. 2017, Leon et al. 2019). In addition, Tac1 neurons appear to mediate the metabolic effects of leptin (Lewis et al. 2016). Thus, it is likely that Tac1 neurons are also involved in the transmission of metabolic signals to reproductive neurons.
It should be noted that the aforementioned populations of neurons with potential effects should not be overlooked, as their involvement under normal physiological conditions would contribute to ultimately modulating the net effect of all inhibitory and stimulatory inputs to the GnRH-driven GnRH neuronal network. Unfortunately, due to the lack of experimental data, the role of the above neurons in controlling reproductive metabolism is still largely unknown and well worth further investigation given the complexity of information transmission in the hypothalamic neuronal network.
The regulation of the metabolic function by reproductive neurons
Reproductive and metabolic systems influence each other, and while we have focused on the metabolic control of fertility, the impact of reproductive signaling itself on the metabolic function is also an important aspect of the integration of energy metabolism and reproduction. Recently, attention has been paid to the nonreproductive role of reproductive neurons such as Kisspeptin neurons and RFRP-3 neurons in the metabolism and energy balance. It is well known that appetite/food intake regulation is the major form of energy accumulation in mammals. Here, we summarize the regulation of hypothalamic Kisspeptin and RFRP-3 on the hypothalamic feeding circuit, in addition to the regulation of reproduction, to deepen our understanding of the integration between energy metabolism and reproductive networks.
Hypothalamic Kiss1 neurons regulate food intake
In recent years, there has been substantial evidence that Kiss1 neurons play a role in the direct regulation of food intake. Central injection of kisspeptin significantly reduced food intake within 3 h in male rats (Saito et al. 2019). The feeding-related neurons POMC/CART and AgRP/NPY are the major projections of Kiss1ARC neurons (Moore et al. 2019, Yee et al. 2019). α-MSH produced by POMC/CART neurons can promote satiety and reduce food intake while increasing energy expenditure. In contrast, AgRP and NPY peptides produced by AgRP/NPY neurons increase food intake and reduce energy expenditure (Barsh & Schwartz 2002). POMC and AgRP neurons express Kiss1r (Talbi & Navarro 2020), and kisspeptin increases the expression of POMC/CART neuron (Cazarez-Marquez et al. 2019). However, the satiety induction of POMC neuronal activation is very slow, typically requiring 24–48 h to inhibit food intake (Andermann & Lowell 2017). Thus, the anorexigenic effect of exogenous kisspeptin may be mediated by AgRP/NPY neurons but not by POMC/CART neurons. In addition, glutamatergic neurons, which use glutamate as a neurotransmitter, constitute the majority of excitatory neurons and occupy a major part of the cerebral cortex (Chuang et al. 2021). Electrophysiological experiments confirmed that Kiss1ARC neurons not only input kisspeptin to POMC/CART and AgRP/NPY neurons but also input glutamate to them. Glutamate mediates the excitation of Kiss1ARC neurons on POMC/CART neurons by activating different metabotropic glutamate receptors while selectively inhibiting AgRP/NPY neurons (Nestor et al. 2016), which eventually led to the inhibition of food intake. Given the anorexigenic effect of Kisspeptin in fasted rodents, it is possible that the removal of Kisspeptin signaling has the opposite effect. Interestingly, however, studies in global Kiss1r KO mice showed completely opposite results to those previously speculated and surprisingly correlated with reduced food intake in both sexes during light and darkness periods (Tolson et al. 2019, Velasco et al. 2019). Subsequent studies have shown that restoring Kiss1r signaling in GnRH neurons of global Kiss1r KO mice alone is not sufficient to alter the metabolic phenotype of reduced feeding, suggesting that reduced feeding in Kiss1r-deficient mice is not dependent on gonadal steroids, at least not primarily responsible (Velasco et al. 2019). Notably, there was a significant sex difference in the inhibitory effect of exogenous Kisspeptin treatment on feeding (Talbi & Navarro 2020). Unfortunately, the reason for this difference remains unclear and, given the multifunctional role of kisspeptin neurons, may be related to the different kisspeptin neuronal distribution and expression in both the sexes. Furthermore, the reason for this discrepancy may also be related to the heterogeneity of downstream neurons in the hypothalamic feeding circuit mediated by Kisspeptin neurons. For example, it has been reported that POMC-specific subtypes drive sexual dimorphism in energy homeostasis (Burke et al. 2016, Wang et al. 2018). Consistently, in a recent study, Gonza´lez-Garcı´a et al. found that estradiol (E2)-sensitive Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1)-expressing POMCARC neurons serve as an important subpopulation that integrates E2-dependent enhancement of leptin anorexia, reflecting gender dimorphism in hypothalamic metabolic control. This study points to Cited1 as an important intracellular transcriptional co-factor that integrates the convergent effects of E2 and leptin on food intake (Gonzalez-Garcia et al. 2023). Although it is not clear whether Cited1 is also involved in the action of Kisspeptin on subpopulations of POMCARC neurons, resulting in gender differences, it suggests that the heterogeneity of neuronal subpopulations and the involvement of specific intracellular transcription factors may play an important role in the hypothalamic feeding circuit mediated by reproductive neurons such as Kisspeptin neurons.
Hypothalamic RFRP-3 neurons regulate food intake
Similarly, GnIH/RFRP-3 is involved in feeding regulation in the hypothalamus. Administration of RFRP-3 via the ICV route has been reported to stimulate feeding in both male and female rats (Murakami et al. 2008). Subsequently, it has also been observed to play an appetitive role in sheep (Clarke et al. 2012), mice (Johnson et al. 2007), and cynomolgus monkeys (Tachibana et al. 2005). The localization of RFRP-3 neurons in the DMH and paraventricular nucleus (PVN) suggests an important role in the energy balance, as these regions of the hypothalamus play an important role in feeding (Morton et al. 2006). Qi et al. (Talbi et al. 2016b) reported that RFRP-3 neurons project to NPY, POMC, orexin, and MCH cells, which are key regulators of food intake and energy status in animals. Patch-clamp electrophysiological experiments performed on rat brain slices fluorescently labeled with POMC and NPY neurons showed that RFRP-3 significantly inhibited the firing rate of POMC neurons (Jacobi et al. 2013). Talbi et al. (Talbi et al. 2016a) reported that ICV injection of RFRP-3 resulted in a four-fold increase in the food intake, a decrease in POMC, and an increase in NPY expression levels in female jerboa rats. Based on this, he proposed that the projection of RFRP-3 exerts a negative effect on appetite-decreasing POMC neurons and a positive effect on appetite-decreasing NPY neurons, thereby increasing food intake in female desert jerboa. Interestingly, it has also been shown that RFRP-3 inhibits the action potential of NPY neurons, which came as a surprise to us because both RFRP-3 and NPY have appetite-stimulating effects (Jacobi et al. 2013). Moreover, in vitro experiments have shown that hypothalamic tissue treated with RFRP-3 can inhibit the secretion of NPY and α-MSH (Jacobi et al. 2013). Similar phenomena have been found in mice, rats, sheep, and nonhuman primates (Clarke et al. 2012). Despite some puzzling points, the available results suggest that RFRP-3-mediated stimulation of food intake and positive energy balance may be primarily due to its inhibitory effect on the POMC neurons.
Conclusion
In this paper, we discuss the central neuroendocrine pathways and mechanisms linking energy metabolism and reproduction, starting with the peripheral metabolic hormones representing energy reserve and the key components of GnRH, kisspeptin, and RFRP-3. GnRH neurons play a reproductive gating role in the function of the reproductive central nervous system, and their activity is regulated by different neuropeptides, forming a central control network. Since reproductive neurons GnRH, Kisspeptin, and RFRP-3 are not the main targets of peripheral metabolic hormones, some metabolic hormone-sensitive neurons and their main neuropeptide products, such as POMC/CART, AgRP/NPY, GABA, NO, orexin, GALP, PACAP, play an important role in mediating peripheral metabolism on reproductive neurons. In addition, as an important aspect of the integration of energy and reproduction, the initiation of reproduction itself must be accompanied by the control of energy balance. Therefore, we also summarized the current research on the hypothalamic feeding circuit involving Kisspeptin and RFRP-3, in order to understand the hypothalamic integration and interaction of energy and reproduction from different perspectives. It is worth noting that the central neuroendocrine circuit that links energy metabolism and reproduction is extremely complex and redundant, and many things remain unclear, such as the target and role of metabolic hormones, the metabolic control of POMC/CART and AgRP/NPY neurons on RFRP-3 neurons. As the only known GnRH inhibitory neuropeptide and potential energy integration center, RFRP-3 needs further study.
Declaration of interest
There is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work was supported by Chongqing Technological Innovation and Application Development Project (Grant No. cstc2019jscx-gksbX0099), the National Key R&D Program of China (Grant No. 2017YFD0501902), and Chongqing Education Commission (KJQN202101433).
Author contribution statement
Fan Yang and Shuang Zhao drafted or revised the manuscript, read and approved the final manuscript, and agreed to be accountable for all aspects of the work. Pingqing Wang and Wei Xiang made substantial contributions to the concept and design of the work.
Acknowledgements
The authors would like to thank all the reviewers who participated in the review and PRS (www.proof-reading-service.com) for its linguistic assistance during the preparation of this manuscript.
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