Accessibility / Report Error

The neuroendocrine pathways and mechanisms for the control of the reproduction in female pigs

Abstract

Within the hypothalamic-pituitary-gonad (HPG) axis, the major hierarchical component is gonadotropin-releasing hormone (GnRH) neurons, which directly or indirectly receive regulatory inputs from a wide array of regulatory signals and pathways, involving numerous circulating hormones, neuropeptides, and neurotransmitters, and which operate as a final output for the brain control of reproduction. In recent years, there has been an increasing interest in neuropeptides that have the potential to stimulate or inhibit GnRH in the hypothalamus of pigs. Among them, Kisspeptin is a key component in the precise regulation of GnRH neuron secretion activity. Besides, other neuropeptides, including neurokinin B (NKB), neuromedin B (NMB), neuromedin S (NMS), α-melanocyte-stimulating hormone (α-MSH), Phoenixin (PNX), show potential for having a stimulating effect on GnRH neurons. On the contrary, RFamide-related peptide-3 (RFRP-3), endogenous opioid peptides (EOP), neuropeptide Y (NPY), and Galanin (GAL) may play an inhibitory role in the regulation of porcine reproductive nerves and may directly or indirectly regulate GnRH neurons. By combining data from suitable model species and pigs, we aim to provide a comprehensive summary of our current understanding of the neuropeptides acting on GnRH neurons, with a particular focus on their central regulatory pathways and underlying molecular basis.

Keywords:
pig; reproduction; neuroendocrine; GnRH neuron; RFamide-related peptide-3

Introduction

The reproductive function of pigs is controlled by complex regulatory networks, which integrate peripheral and internal cues and impinge at the brain centers driving the reproductive axis. GnRH is synthesized in a small subset of hypothalamic neurons, which form the final common pathway for the central control of reproduction (Herbison 2016Herbison AE. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat Rev Endocrinol. 2016;12(8):452-66. http://dx.doi.org/10.1038/nrendo.2016.70. PMid:27199290.
http://dx.doi.org/10.1038/nrendo.2016.70...
). They integrate steroidal, lactational, hunger, stress, satiety, circadian, odorant, and pheromone signals (Spergel 2019Spergel DJ. Neuropeptidergic modulation of GnRH neuronal activity and GnRH secretion controlling reproduction: insights from recent mouse studies. Cell Tissue Res. 2019;375(1):179-91. http://dx.doi.org/10.1007/s00441-018-2893-z. PMid:30078104.
http://dx.doi.org/10.1007/s00441-018-289...
). These signals are conveyed to a large extent by neuropeptides directly and/or indirectly, as well as by conventional neurotransmitters, gaseous transmitters, gliotransmitters, and other factors. GnRH neurons synthesize and secrete GnRH in a pulsatile manner from axon terminals in the median eminence (ME) into the hypothalamo-hypophyseal circulation through which it is transported to the anterior pituitary gland. By binding to specific receptors (gonadotropin-releasing hormone receptors, GnRHRs) on pituitary gonadotropin cells, GnRH stimulates the biosynthesis and the release of two gonadotropins (luteinizing hormone, LH; follicle-stimulating hormone, FSH). LH and FSH, which are required for the development and maintenance of the gonads and thus for fertility, bind to receptors on the gonads to regulate gametogenesis and gonadal steroidogenesis in both sexes (Millar 2005Millar RP. GnRHs and GnRH receptors. Anim Reprod Sci. 2005;88(1–2):5-28. http://dx.doi.org/10.1016/j.anireprosci.2005.05.032. PMid:16140177.
http://dx.doi.org/10.1016/j.anireprosci....
; Muro et al., 2021Muro BBD, Leal DF, Carnevale RF, Torres MA, Mendonça MV, Nakasone DH, Martinez CHG, Ravagnani GM, Monteiro MS, Poor AP, Martins SMMK, Viau P, Oliveira CA, Castro RVG, Bessi BW, Bressan FF, Pulz LH, Strefezzi RF, Almond GW, Andrade AFC. Altrenogest during early pregnancy modulates uterine glandular epithelium and endometrial growth factor expression at the time implantation in pigs. Anim Reprod. 2021;18(1):e20200431. http://dx.doi.org/10.1590/1984-3143-ar2020-0431. PMid:34122654.
http://dx.doi.org/10.1590/1984-3143-ar20...
).

Extensive research has shown that several neuropeptides have been viewed as modulators or regulators of GnRH neurons in the porcine hypothalamus, including Kisspeptins, which have a stimulating effect on the activity and synthesis of GnRH neurons, and RFamide-related peptide-3 (RFRP-3; gonadotropin inhibitory hormone, GnIH), which has an inhibitory effect on the activity and synthesis of GnRH neurons (Herbison 2016Herbison AE. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat Rev Endocrinol. 2016;12(8):452-66. http://dx.doi.org/10.1038/nrendo.2016.70. PMid:27199290.
http://dx.doi.org/10.1038/nrendo.2016.70...
). It is now well established from a variety of studies, that the coordination effect of excitatory neuronal signaling coupled with inhibitor neuronal input to the GnRH pulse generator controls the function of the HPG axis, thereby driving and maintaining the reproductive ability of pigs (Spergel 2019Spergel DJ. Neuropeptidergic modulation of GnRH neuronal activity and GnRH secretion controlling reproduction: insights from recent mouse studies. Cell Tissue Res. 2019;375(1):179-91. http://dx.doi.org/10.1007/s00441-018-2893-z. PMid:30078104.
http://dx.doi.org/10.1007/s00441-018-289...
). Although recent advancements in neuropeptides that regulate porcine GnRH have been made, our understanding of the central nervous system network of porcine reproduction remains incomplete. This review focuses on the neuropeptides which have been viewed as regulators of GnRH neuronal activity and/ or reproductive function and whether they act directly on GnRH neurons in pigs. The complete elucidation of the novel neuropeptidergic and molecular mechanisms summarized in this review will not only expand our knowledge of the intimate mechanisms responsible for the reproductive in pigs but might also provide new tools and targets for better prevention and management of pig reproduction in practice (Peltoniemi et al., 2019Peltoniemi O, Björkman S, Oropeza-Moe M, Oliviero C. Developments of reproductive management and biotechnology in the pig. Anim Reprod. 2019;16(3):524-38. http://dx.doi.org/10.21451/1984-3143-AR2019-0055. PMid:32435295.
http://dx.doi.org/10.21451/1984-3143-AR2...
).

The important role of gonadotropin-releasing hormone (GnRH) neurons in pig reproduction

The activation of the hypothalamic-pituitary axis is critical for the initiation and maintenance of reproductive cycles in pigs and is influenced by a number of factors, such as nutrition, metabolism, and gonadal steroids (Garcia et al., 2020Garcia IS, Teixeira SA, Costa KA, Marques DBD, Rodrigues GA, Costa TC, Guimarães JD, Otto PI, Saraiva A, Ibelli AMG, Cantão ME, Oliveira HC, Ledur MC, Peixoto JO, Guimarães SEF. L‐Arginine supplementation of gilts during early gestation modulates energy sensitive pathways in pig conceptuses. Mol Reprod Dev. 2020;87(7):819-34. http://dx.doi.org/10.1002/mrd.23397. PMid:32592179.
http://dx.doi.org/10.1002/mrd.23397...
; Marín-García and Llobat 2021Marín-García PJ, Llobat L. How does protein nutrition affect the epigenetic changes in pig? A review. Animals (Basel). 2021;11(2):544. http://dx.doi.org/10.3390/ani11020544. PMid:33669864.
http://dx.doi.org/10.3390/ani11020544...
). At present, it is universally admitted that GnRH neurons in pigs function as brain sensors and main effectors for the modulation of the hypothalamus level. The cell bodies of GnRH neurons, which receive neuropeptidergic inputs from neurons in the hypothalamus and other brain areas, are distributed in the preoptic area (POA) at the organum vasculosum of the lamina terminalis (OVLT) level, medial basal hypothalamus (MBH) including the arcuate nucleus (ARC), and in the anterior hypothalamic area (AHA) (Lents et al., 2020Lents CA, Lindo AN, Hileman SM, Nonneman DJ. Physiological and genomic insight into neuroendocrine regulation of puberty in gilts. Domest Anim Endocrinol. 2020;73:106446. http://dx.doi.org/10.1016/j.domaniend.2020.106446. PMid:32199704.
http://dx.doi.org/10.1016/j.domaniend.20...
).

In pigs, GnRH pulsation is essential for maintaining gonadotropin gene expression and the physiological pattern of gonadotropin secretion. The pulse frequencies of GnRH and LH are known to change throughout the estrous cycle and postpartum period. In the luteal phase of gilts, a pattern of LH secretion characterized by high-amplitude, low-frequency pulses, and reduced serum concentrations of LH,as well as increased serum concentrations of FSH were associated with the low-frequency GnRH pulse. In the follicular phase of gilts, the transition of the GnRH pulse mode to a high frequency resulting in the pattern of LH secretion changing to high-frequency, low-amplitude pulses, and a decrease in FSH synthesis and release. The interaction between GnRH and LH/FSH found that the synthesis and pulsatile secretion of GnRH from neurons in the hypothalamus drives pulsatile secretion of LH, and to a lesser extent, FSH in gilts (Tsutsumi and Webster 2009Tsutsumi R, Webster NJG. GnRH pulsatility, the pituitary response and reproductive dysfunction. Endocr J. 2009;56(6):729-37. http://dx.doi.org/10.1507/endocrj.K09E-185. PMid:19609045.
http://dx.doi.org/10.1507/endocrj.K09E-1...
).

Neuropeptide modulators of GnRH neuronal activity, GnRH secretion and reproduction that act directly on GnRH neurons

Kisspeptin

Kisspeptin is the peptide encoded by the KISS1 gene, and the Kisspeptin receptor is a G-protein-coupled receptor, GPR54 (Ohtaki et al., 2001Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411(6837):613-7. http://dx.doi.org/10.1038/35079135. PMid:11385580.
http://dx.doi.org/10.1038/35079135...
; Seminara et al., 2003Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MBL, Crowley WF Jr, Aparicio SAJR, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614-27. http://dx.doi.org/10.1056/NEJMoa035322. PMid:14573733.
http://dx.doi.org/10.1056/NEJMoa035322...
). Kisspeptin has emerged as a key regulator of reproductive function in pigs when it was discovered that boars in which a functional Kisspeptin receptor was knocked out with gene-editing technology presented a condition of hypogonadotropic hypogonadism (Sonstegard et al., 2017Sonstegard T, Fahrenkrug S, Carlson D. Precision animal breeding to make genetically castrated animals for improved animal welfare and alternative breeding applications. J Anim Sci. 2017;95(suppl 2):149-50. http://dx.doi.org/10.2527/asasmw.2017.307.
http://dx.doi.org/10.2527/asasmw.2017.30...
). The boars are characterized by a lack of gonadal development and low levels of gonadotropin secretion from the anterior pituitary gland that failed to transition through puberty (de Roux et al., 2003de Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA. 2003;100(19):10972-6. http://dx.doi.org/10.1073/pnas.1834399100. PMid:12944565.
http://dx.doi.org/10.1073/pnas.183439910...
; Semple et al., 2005Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O’rahilly S, Aparicio SA. Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2005;90(3):1849-55. http://dx.doi.org/10.1210/jc.2004-1418. PMid:15598687.
http://dx.doi.org/10.1210/jc.2004-1418...
). A substantial body of evidence indicates that Kisspeptin has potent stimulatory action on the secretion of gonadotropin hormones in gilts (Lents et al., 2008Lents CA, Heidorn NL, Barb CR, Ford JJ. Central and peripheral administration of kisspeptin activates gonadotropin but not somatotropin secretion in prepubertal gilts. Reproduction. 2008;135(6):879-87. http://dx.doi.org/10.1530/REP-07-0502. PMid:18339687.
http://dx.doi.org/10.1530/REP-07-0502...
; Ralph et al., 2017Ralph C, Kirkwood R, Tilbrook A. A single intravenous injection of Kisspeptin evokes an increase in luteinising hormone in 15- and 18- week-old gilts. Anim Reprod Sci. 2017;57(12):2469. http://dx.doi.org/10.1071/ANv57n12Ab067.
http://dx.doi.org/10.1071/ANv57n12Ab067...
). Likewise, accumulating evidence showed that central and peripheral treatment with Kisspeptin stimulated gonadotropin secretion, particularly LH secretion, in various mammalian species, including rodents, sheep, goats, cattle, and horses (Thompson et al., 2004Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA, Bloom SR. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2004;16(10):850-8. http://dx.doi.org/10.1111/j.1365-2826.2004.01240.x. PMid:15500545.
http://dx.doi.org/10.1111/j.1365-2826.20...
; Messager et al., 2005Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA. 2005;102(5):1761-6. http://dx.doi.org/10.1073/pnas.0409330102. PMid:15665093.
http://dx.doi.org/10.1073/pnas.040933010...
; Shahab et al., 2005Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: A potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA. 2005;102(6):2129-34. http://dx.doi.org/10.1073/pnas.0409822102. PMid:15684075.
http://dx.doi.org/10.1073/pnas.040982210...
; Caraty et al., 2007Caraty A, Smith JT, Lomet D, Ben Saïd S, Morrissey A, Cognie J, Doughton B, Baril G, Briant C, Clarke IJ. Kisspeptin Synchronizes Preovulatory Surges in Cyclical Ewes and Causes Ovulation in Seasonally Acyclic Ewes. Endocrinology. 2007;148(11):5258-67. http://dx.doi.org/10.1210/en.2007-0554. PMid:17702853.
http://dx.doi.org/10.1210/en.2007-0554...
; Kadokawa et al., 2008Kadokawa H, Matsui M, Hayashi K, Matsunaga N, Kawashima C, Shimizu T, Kida K, Miyamoto A. Peripheral administration of kisspeptin-10 increases plasma concentrations of GH as well as LH in prepubertal Holstein heifers. J Endocrinol. 2008;196(2):331-4. http://dx.doi.org/10.1677/JOE-07-0504. PMid:18252956.
http://dx.doi.org/10.1677/JOE-07-0504...
; Magee et al., 2009Magee C, Foradori CD, Bruemmer JE, Arreguin-Arevalo JA, McCue PM, Handa RJ, Squires EL, Clay CM. Biological and anatomical evidence for kisspeptin regulation of the hypothalamic-pituitary-gonadal axis of estrous horse mares. Endocrinology. 2009;150(6):2813-21. http://dx.doi.org/10.1210/en.2008-1698. PMid:19228887.
http://dx.doi.org/10.1210/en.2008-1698...
; Hashizume et al., 2010Hashizume T, Saito H, Sawada T, Yaegashi T, Ezzat AA, Sawai K, Yamashita T. Characteristics of stimulation of gonadotropin secretion by kisspeptin-10 in female goats. Anim Reprod Sci. 2010;118(1):37-41. http://dx.doi.org/10.1016/j.anireprosci.2009.05.017. PMid:19574004.
http://dx.doi.org/10.1016/j.anireprosci....
). In sheep, Kisspeptin receptor is expressed in the GnRH neurons of the hypothalamus, and intracerebroventricular infusion of Kisspeptin caused a dramatic increase in serum LH and FSH,accompanied by a concomitant release of the cerebrospinal fluid GnRH content (Messager et al., 2005Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA. 2005;102(5):1761-6. http://dx.doi.org/10.1073/pnas.0409330102. PMid:15665093.
http://dx.doi.org/10.1073/pnas.040933010...
; Caraty et al., 2007Caraty A, Smith JT, Lomet D, Ben Saïd S, Morrissey A, Cognie J, Doughton B, Baril G, Briant C, Clarke IJ. Kisspeptin Synchronizes Preovulatory Surges in Cyclical Ewes and Causes Ovulation in Seasonally Acyclic Ewes. Endocrinology. 2007;148(11):5258-67. http://dx.doi.org/10.1210/en.2007-0554. PMid:17702853.
http://dx.doi.org/10.1210/en.2007-0554...
; Smith et al., 2011Smith JT, Li Q, Yap KS, Shahab M, Roseweir AK, Millar RP, Clarke IJ. Kisspeptin is essential for the full preovulatory LH surge and stimulates GnRH release from the isolated ovine median eminence. Endocrinology. 2011;152(3):1001-12. http://dx.doi.org/10.1210/en.2010-1225. PMid:21239443.
http://dx.doi.org/10.1210/en.2010-1225...
). Moreover, Kisspeptin-induced LH secretion was abolished in ewes treated with neutralizing antibodies to GnRH, and in ewes in which the hypothalamus had been disconnected from the pituitary to eliminate GnRH input to gonadotroph cells, indicating that Kisspeptin stimulates LH secretion in a GnRH-dependent manner (Arreguin-Arevalo et al., 2007Arreguin-Arevalo JA, Lents CA, Farmerie TA, Nett TM, Clay CM. KiSS-1 peptide induces release of LH by a direct effect on the hypothalamus of ovariectomized ewes. Anim Reprod Sci. 2007;101(3-4):265-75. http://dx.doi.org/10.1016/j.anireprosci.2006.09.021. PMid:17055196.
http://dx.doi.org/10.1016/j.anireprosci....
; Smith et al., 2008bSmith JT, Rao A, Pereira A, Caraty A, Millar RP, Clarke IJ. Kisspeptin is present in ovine hypophysial portal blood but does not increase during the preovulatory luteinizing hormone surge: evidence that gonadotropes are not direct targets of kisspeptin in vivo. Endocrinology. 2008b;149(4):1951-9. http://dx.doi.org/10.1210/en.2007-1425. PMid:18162520.
http://dx.doi.org/10.1210/en.2007-1425...
). Although there are no similar studies in pigs, the direct action of Kisspeptin on GnRH neurons is also inferred from the spatial distribution of the Kisspeptin expression within the porcine hypothalamus.

The localization of the Kisspeptin expression within the porcine hypothalamus has not been fully characterized (Lents 2019Lents CA. Review: kisspeptin and reproduction in the pig. Animal. 2019;13(12):2986-99. http://dx.doi.org/10.1017/S1751731119001666. PMid:31317853.
http://dx.doi.org/10.1017/S1751731119001...
). In the central nervous system of pigs, Kisspeptin cells are localized primarily in two discrete regions involved in the regulation of gonadotropin secretion, including the MBH within the ARC and the periventricular (PeV) nucleus (Tomikawa et al., 2010Tomikawa J, Homma T, Tajima S, Shibata T, Inamoto Y, Takase K, Inoue N, Ohkura S, Uenoyama Y, Maeda K, Tsukamura H. Molecular characterization and estrogen regulation of hypothalamic KISS1 gene in the pig. Biol Reprod. 2010;82(2):313-9. http://dx.doi.org/10.1095/biolreprod.109.079863. PMid:19828777.
http://dx.doi.org/10.1095/biolreprod.109...
; Ieda et al., 2014Ieda N, Uenoyama Y, Tajima Y, Nakata T, Kano M, Naniwa Y, Watanabe Y, Minabe S, Tomikawa J, Inoue N, Matsuda F, Ohkura S, Maeda K, Tsukamura H. KISS1 Gene Expression in the Developing Brain of Female Pigs in Pre- and Peripubertal Periods. J Reprod Dev. 2014;60(4):312-6. http://dx.doi.org/10.1262/jrd.2013-129. PMid:24909600.
http://dx.doi.org/10.1262/jrd.2013-129...
; Thorson et al., 2017Thorson JF, Heidorn NL, Ryu V, Czaja K, Nonneman DJ, Barb CR, Hausman GJ, Rohrer GA, Prezotto LD, McCosh RB, Wright EC, White BR, Freking BA, Oliver WT, Hileman SM, Lents CA. Relationship of neuropeptide FF receptors with pubertal maturation of gilts. Biol Reprod. 2017;96(3):617-34. http://dx.doi.org/10.1095/biolreprod.116.144998. PMid:28339619.
http://dx.doi.org/10.1095/biolreprod.116...
). Within the ARC of the pig, a spatially distinct pattern of KISS1 is seen, with the greatest expression occurring in the medio-caudal sections, similar to the ARC distribution of Kisspeptin observed in sheep and cattle (Redmond et al., 2011Redmond JS, Baez-Sandoval GM, Spell KM, Spencer TE, Lents CA, Williams GL, Amstalden M. Developmental Changes in Hypothalamic Kiss1 Expression during Activation of the Pulsatile Release of Luteinising Hormone in Maturing Ewe Lambs. J Neuroendocrinol. 2011;23(9):815-22. http://dx.doi.org/10.1111/j.1365-2826.2011.02177.x. PMid:21679258.
http://dx.doi.org/10.1111/j.1365-2826.20...
; Cardoso et al., 2015Cardoso RC, Alves BRC, Sharpton SM, Williams GL, Amstalden M. Nutritional programming of accelerated puberty in heifers: involvement of pro‐opiomelanocortin neurones in the arcuate nucleus. J Neuroendocrinol. 2015;37(8):647-57. http://dx.doi.org/10.1111/jne.12291. PMid:25944025.
http://dx.doi.org/10.1111/jne.12291...
; Lents et al., 2020Lents CA, Lindo AN, Hileman SM, Nonneman DJ. Physiological and genomic insight into neuroendocrine regulation of puberty in gilts. Domest Anim Endocrinol. 2020;73:106446. http://dx.doi.org/10.1016/j.domaniend.2020.106446. PMid:32199704.
http://dx.doi.org/10.1016/j.domaniend.20...
). Preliminary immunocytochemistry data illustrate that neuronal cell bodies as well as nerve fibers for Kisspeptin are evident in the porcine ARC. Thus, it is anticipated that the neuroanatomical distribution of Kisspeptin neurons in the porcine ARC is like that of other species. Specifically, Kisspeptin neurons in the POA regulate GnRH cell bodies, whereas Kisspeptin neurons in the ARC act on GnRH terminal axons in the median eminence (Lents et al., 2020Lents CA, Lindo AN, Hileman SM, Nonneman DJ. Physiological and genomic insight into neuroendocrine regulation of puberty in gilts. Domest Anim Endocrinol. 2020;73:106446. http://dx.doi.org/10.1016/j.domaniend.2020.106446. PMid:32199704.
http://dx.doi.org/10.1016/j.domaniend.20...
).

Estradiol has a biphasic effect in pigs, inhibiting basal LH pulses via negative feedback then stimulating an ovulatory surge of LH through positive feedback (Ieda et al., 2014Ieda N, Uenoyama Y, Tajima Y, Nakata T, Kano M, Naniwa Y, Watanabe Y, Minabe S, Tomikawa J, Inoue N, Matsuda F, Ohkura S, Maeda K, Tsukamura H. KISS1 Gene Expression in the Developing Brain of Female Pigs in Pre- and Peripubertal Periods. J Reprod Dev. 2014;60(4):312-6. http://dx.doi.org/10.1262/jrd.2013-129. PMid:24909600.
http://dx.doi.org/10.1262/jrd.2013-129...
; Thorson et al., 2017Thorson JF, Heidorn NL, Ryu V, Czaja K, Nonneman DJ, Barb CR, Hausman GJ, Rohrer GA, Prezotto LD, McCosh RB, Wright EC, White BR, Freking BA, Oliver WT, Hileman SM, Lents CA. Relationship of neuropeptide FF receptors with pubertal maturation of gilts. Biol Reprod. 2017;96(3):617-34. http://dx.doi.org/10.1095/biolreprod.116.144998. PMid:28339619.
http://dx.doi.org/10.1095/biolreprod.116...
). When sexually mature OVX gilts were given a dose of estradiol sufficient to stimulate an ovulatory surge of LH, the expression of Kisspeptin in the PeV was upregulated compared with control OVX gilts (Tomikawa et al., 2010Tomikawa J, Homma T, Tajima S, Shibata T, Inamoto Y, Takase K, Inoue N, Ohkura S, Uenoyama Y, Maeda K, Tsukamura H. Molecular characterization and estrogen regulation of hypothalamic KISS1 gene in the pig. Biol Reprod. 2010;82(2):313-9. http://dx.doi.org/10.1095/biolreprod.109.079863. PMid:19828777.
http://dx.doi.org/10.1095/biolreprod.109...
; Silva et al., 2021Silva PCP, Brasil OO, Souto PLG, Moreira NH, Silva JP, Silva BDM, Ramos AF. Fixed-time artificial insemination protocols on brazilian locally adapted breed gilts on ovulatory response and embryo production. Anim Reprod. 2021;18(1):e20200776. http://dx.doi.org/10.1590/1984-3143-ar2020-0776. PMid:34122655.
http://dx.doi.org/10.1590/1984-3143-ar20...
). It is inferred that separate populations of Kisspeptin neurons in the ARC and the PeV of gilts mediate negative and positive estrogen feedback for the control of tonic and surge LH secretion, respectively. Moreover, previous research has established that the initiation of puberty and postpartum reproductive cycles in gilts are metabolically gated. Recent work by Thorson et al. (2018)Thorson JF, Prezotto LD, Adams H, Petersen SL, Clapper JA, Wright EC, Oliver WT, Freking BA, Foote AP, Berry ED, Nonneman DJ, Lents CA. Energy balance affects pulsatile secretion of luteinizing hormone from the adenohypophesis and expression of neurokinin B in the hypothalamus of ovariectomized gilts†. Biol Reprod. 2018;99(2):433-45. http://dx.doi.org/10.1093/biolre/ioy069. PMid:30101293.
http://dx.doi.org/10.1093/biolre/ioy069...
has established that short-term (10 days) negative energy balance induced reduced frequency and increased amplitude of LH pulses, but no differences in ARC the transcription of Kisspeptin between feed-restricted and full-fed gilts were observed (Thorson et al., 2018Thorson JF, Prezotto LD, Adams H, Petersen SL, Clapper JA, Wright EC, Oliver WT, Freking BA, Foote AP, Berry ED, Nonneman DJ, Lents CA. Energy balance affects pulsatile secretion of luteinizing hormone from the adenohypophesis and expression of neurokinin B in the hypothalamus of ovariectomized gilts†. Biol Reprod. 2018;99(2):433-45. http://dx.doi.org/10.1093/biolre/ioy069. PMid:30101293.
http://dx.doi.org/10.1093/biolre/ioy069...
). Surveys such as that conducted by Zhou et al. (2014)Zhou D, Zhuo Y, Che L, Lin Y, Fang Z, Wu D. Nutrient restriction induces failure of reproductive function and molecular changes in hypothalamus–pituitary–gonadal axis in postpubertal gilts. Mol Biol Rep. 2014;41(7):4733-42. http://dx.doi.org/10.1007/s11033-014-3344-x. PMid:24728609.
http://dx.doi.org/10.1007/s11033-014-334...
have shown that feed restriction to cyclic gilts for a prolonged period (100 days) resulted in the point that they ceased cycling, and mRNA expressions for Kisspeptin, Kisspeptin receptor, and GnRH were all downregulated in the MBH; on the contrary, Kisspeptin and its receptor mRNA expression were upregulated in the hypothalamic tissue containing the caudal POA and PeV of pigs fed a higher-energy diet (Zhou et al., 2014Zhou D, Zhuo Y, Che L, Lin Y, Fang Z, Wu D. Nutrient restriction induces failure of reproductive function and molecular changes in hypothalamus–pituitary–gonadal axis in postpubertal gilts. Mol Biol Rep. 2014;41(7):4733-42. http://dx.doi.org/10.1007/s11033-014-3344-x. PMid:24728609.
http://dx.doi.org/10.1007/s11033-014-334...
). This implies that nutrition-induced changes in LH pulse patterns of pigs may depend on hypothalamic subpopulations of Kisspeptin neurons that respond differently to nutritional signals in mediating the GnRH pulse generator.

α-Melanocyte-stimulating hormone (α-MSH)

The anorexigenic neuropeptide α-MSH is synthesized and released by pro-opiomelanocortin (POMC) neurons and the α-MSH analogue melanotan II, which act directly via MC3Rs and MC4Rs on most (70%) GnRH neurons to increase their firing rate and induce the expression of c-Fos in rats (Israel et al., 2012Israel DD, Sheffer-Babila S, de Luca C, Jo Y-H, Liu SM, Xia Q, Spergel DJ, Dun SL, Dun NJ, Chua SC Jr. Effects of Leptin and Melanocortin Signaling Interactions on Pubertal Development and Reproduction. Endocrinology. 2012;153(5):2408-19. http://dx.doi.org/10.1210/en.2011-1822. PMid:22408174.
http://dx.doi.org/10.1210/en.2011-1822...
; Roa and Herbison 2012Roa J, Herbison AE. Direct regulation of gnrh neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology. 2012;153(11):5587-99. http://dx.doi.org/10.1210/en.2012-1470. PMid:22948210.
http://dx.doi.org/10.1210/en.2012-1470...
; Lane and Whitaker 2018Lane RL, Whitaker BD. Melatonin and tannic acid supplementation in vitro improve fertilization and embryonic development in pigs. Anim Reprod. 2018;15(2):118-23. http://dx.doi.org/10.21451/1984-3143-AR2016-937. PMid:34122642.
http://dx.doi.org/10.21451/1984-3143-AR2...
; Spergel 2019Spergel DJ. Neuropeptidergic modulation of GnRH neuronal activity and GnRH secretion controlling reproduction: insights from recent mouse studies. Cell Tissue Res. 2019;375(1):179-91. http://dx.doi.org/10.1007/s00441-018-2893-z. PMid:30078104.
http://dx.doi.org/10.1007/s00441-018-289...
; Xu et al., 2021Xu G, Li J, Zhang D, Su T, Li X, Cui S. HSP70 inhibits pig pituitary gonadotrophin synthesis and secretion by regulating the corticotropin-releasing hormone signaling pathway and targeting SMAD3. Domest Anim Endocrinol. 2021;74:106533. http://dx.doi.org/10.1016/j.domaniend.2020.106533. PMid:32992141.
http://dx.doi.org/10.1016/j.domaniend.20...
). In pigs, the distribution and location of POMC perikarya are identified specifically within and around the immediate location of the ARC. Fibers for POMC were noted as projecting rostrally from the ARC to the SCN, SOP, LHA, medial POA, and dbB (Lents et al., 2020Lents CA, Lindo AN, Hileman SM, Nonneman DJ. Physiological and genomic insight into neuroendocrine regulation of puberty in gilts. Domest Anim Endocrinol. 2020;73:106446. http://dx.doi.org/10.1016/j.domaniend.2020.106446. PMid:32199704.
http://dx.doi.org/10.1016/j.domaniend.20...
). GnRH neurons in the hypothalamus of gilts showed numerous close contacts with POMC-containing varicosities, and both GnRH and POMC fibers have extensive overlap within the ME, supporting the expectation that α-MSH may control the release of GnRH and(or) Kisspeptin for increased LH pulses. Neither ICV treatment of prepubertal OVX gilts with a melanocortin agonist (NDP-MSH) or SHU9119 affected LH secretion, offering contradictory findings (Barb et al., 2004Barb CR, Robertson AS, Barrett JB, Kraeling RR, Houseknecht KL. The role of melanocortin-3 and -4 receptor in regulating appetite, energy homeostasis and neuroendocrine function in the pig. J Endocrinol. 2004;181(1):39-52. http://dx.doi.org/10.1677/joe.0.1810039. PMid:15072565.
http://dx.doi.org/10.1677/joe.0.1810039...
). Moreover, NPY expression increased, while promelanin-concentrating hormone expression decreased with no change in AGRP and POMC expression in NDP-MSH-treated pigs, suggesting α-MSH may is involved in regulating energy homeostasis to reproduction in pigs(Barb et al.,, 2010Barb CR, Hausman GJ, Rekaya R, Lents CA, Lkhagvadorj S, Qu L, Cai W, Couture OP, Anderson LL, Dekkers JC, Tuggle CK. Gene expression in hypothalamus, liver, and adipose tissues and food intake response to melanocortin-4 receptor agonist in pigs expressing melanocortin-4 receptor mutations. Physiol Genomics. 2010;41(3):254-68. http://dx.doi.org/10.1152/physiolgenomics.00006.2010. PMid:20215418.
http://dx.doi.org/10.1152/physiolgenomic...
).

RFamide-related peptide-3 (RFRP-3)

The RFamide-related peptide (RFRP) gene, an ortholog to the gonadotropin-inhibiting hormone (GnIH) gene that was first detected in the hypothalamic–hypophysial system of avian species and regulates avian reproduction by decreasing gonadotropin release and synthesis by acting on the GnRH system and the anterior pituitary gland, was found to encode 3 biological peptides, RFRP-1, RFRP-2, and RFRP-3 (Hinuma et al., 2000Hinuma S, Shintani Y, Fukusumi S, Iijima N, Matsumoto Y, Hosoya M, Fujii R, Watanabe T, Kikuchi K, Terao Y, Yano T, Yamamoto T, Kawamata Y, Habata Y, Asada M, Kitada C, Kurokawa T, Onda H, Nishimura O, Tanaka M, Ibata Y, Fujino M. New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals. Nat Cell Biol. 2000;2(10):703-8. http://dx.doi.org/10.1038/35036326. PMid:11025660.
http://dx.doi.org/10.1038/35036326...
; Legagneux et al., 2009Legagneux K, Bernard-Franchi G, Poncet F, La Roche A, Colard C, Fellmann D, Pralong F, Risold PY. Distribution and genesis of the RFRP-producing neurons in the rat brain: comparison with melanin-concentrating hormone- and hypocretin-containing neurons. Neuropeptides. 2009;43(1):13-9. http://dx.doi.org/10.1016/j.npep.2008.11.001. PMid:19101033.
http://dx.doi.org/10.1016/j.npep.2008.11...
). The receptors of RFRP widely distributed in the central nervous system, pituitary, and gonads in pigs include GPR147 or NPFF1R, the canonical receptor for RFRP, and GPR74 or NPFF2R albeit with much less potency (Yoshida et al., 2003Yoshida H, Habata Y, Hosoya M, Kawamata Y, Kitada C, Hinuma S. Molecular properties of endogenous RFamide-related peptide-3 and its interaction with receptors. Biochim Biophys Acta. 2003;1593(2-3):151-7. PMid:12581859.; Bentley et al., 2010Bentley GE, Tsutsui K, Kriegsfeld LJ. Recent studies of gonadotropin-inhibitory hormone (GnIH) in the mammalian hypothalamus, pituitary and gonads. Brain Res. 2010;1364:62-71. http://dx.doi.org/10.1016/j.brainres.2010.10.001. PMid:20934414.
http://dx.doi.org/10.1016/j.brainres.201...
). Compelling evidence has documented a role of RFRP-3 in regulating GnRH and GHRH neuronal expression and function as well as secretion of gonadotrophin and steroid hormones and impacting the expression of Kisspeptin in mammals (Johnson et al., 2007Johnson MA, Tsutsui K, Fraley GS. Rat RFamide-related peptide-3 stimulates GH secretion, inhibits LH secretion, and has variable effects on sex behavior in the adult male rat. Horm Behav. 2007;51(1):171-80. http://dx.doi.org/10.1016/j.yhbeh.2006.09.009. PMid:17113584.
http://dx.doi.org/10.1016/j.yhbeh.2006.0...
; Ducret et al., 2009Ducret E, Anderson GM, Herbison AE. RFamide-related peptide-3, a mammalian gonadotropin-inhibitory hormone ortholog, regulates gonadotropin-releasing hormone neuron firing in the mouse. Endocrinology. 2009;150(6):2799-804. http://dx.doi.org/10.1210/en.2008-1623. PMid:19131572.
http://dx.doi.org/10.1210/en.2008-1623...
; Kadokawa et al., 2009Kadokawa H, Shibata M, Tanaka Y, Kojima T, Matsumoto K, Oshima K, Yamamoto N. Bovine C-terminal octapeptide of RFamide-related peptide-3 suppresses luteinizing hormone (LH) secretion from the pituitary as well as pulsatile LH secretion in bovines. Domest Anim Endocrinol. 2009;36(4):219-24. http://dx.doi.org/10.1016/j.domaniend.2009.02.001. PMid:19328642.
http://dx.doi.org/10.1016/j.domaniend.20...
; Ancel et al., 2012Ancel C, Bentsen AH, Sébert M-E, Tena-Sempere M, Mikkelsen JD, Simonneaux V. Stimulatory effect of RFRP-3 on the gonadotrophic axis in the male syrian hamster: the exception proves the rule. Endocrinology. 2012;153(3):1352-63. http://dx.doi.org/10.1210/en.2011-1622. PMid:22275511.
http://dx.doi.org/10.1210/en.2011-1622...
; Li et al., 2013Li X, Su J, Fang R, Zheng L, Lei R, Wang X, Lei Z, Jin M, Jiao Y, Hou Y, Guo T, Ma Z. The effects of RFRP-3, the mammalian ortholog of GnIH, on the female pig reproductive axis in vitro. Mol Cell Endocrinol. 2013;372(1-2):65-72. http://dx.doi.org/10.1016/j.mce.2013.03.015. PMid:23541949.
http://dx.doi.org/10.1016/j.mce.2013.03....
). The pig RFRP gene was found to be abundantly expressed in the nervous system (cerebellum, cerebrum, hypothalamus, and pituitary) and reproduction system (ovary, oviduct, uterus, and testis), and is thought to be a candidate gene for porcine reproductive traits (Fang et al., 2014Fang MX, Huang YS, Ye J, Zhang W, Li Y, Nie QH. Identification and characterization of RFRP gene in pigs and its association with reproductive traits. Genet Mol Res. 2014;13(1):1661-71. http://dx.doi.org/10.4238/2014.January.14.8. PMid:24446341.
http://dx.doi.org/10.4238/2014.January.1...
).

Using in situ hybridization and immunohistochemistry, the spatial distribution of RFRP has been investigated in the porcine hypothalamus. RFRP-ir neuronal cell bodies and nerve fibers were located in the posterior hypothalamus, dorsomedial hypothalamic nucleus (DMH), and ventromedial hypothalamic nucleus (VMH), with a similar distribution as that in the brain of rodents, sheep, and mares (Yano et al., 2003Yano T, Iijima N, Kakihara K, Hinuma S, Tanaka M, Ibata Y. Localization and neuronal response of RFamide related peptides in the rat central nervous system. Brain Res. 2003;982(2):156-67. http://dx.doi.org/10.1016/S0006-8993(03)02877-4. PMid:12915251.
http://dx.doi.org/10.1016/S0006-8993(03)...
; Kriegsfeld et al., 2006Kriegsfeld LJ, Mei DF, Bentley GE, Ubuka T, Mason AO, Inoue K, Ukena K, Tsutsui K, Silver R. Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals. Proc Natl Acad Sci USA. 2006;103(7):2410-5. http://dx.doi.org/10.1073/pnas.0511003103. PMid:16467147.
http://dx.doi.org/10.1073/pnas.051100310...
; Gibson et al., 2008Gibson EM, Humber SA, Jain S, Williams WP 3rd, Zhao S, Bentley GE, Tsutsui K, Kriegsfeld LJ. Alterations in RFamide-related peptide expression are coordinated with the preovulatory luteinizing hormone surge. Endocrinology. 2008;149(10):4958-69. http://dx.doi.org/10.1210/en.2008-0316. PMid:18566114.
http://dx.doi.org/10.1210/en.2008-0316...
; Smith et al., 2008aSmith JT, Coolen LM, Kriegsfeld LJ, Sari IP, Jaafarzadehshirazi MR, Maltby M, Bateman K, Goodman RL, Tilbrook AJ, Ubuka T, Bentley GE, Clarke IJ, Lehman MN. Variation in Kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology. 2008a;149(11):5770-82. http://dx.doi.org/10.1210/en.2008-0581. PMid:18617612.
http://dx.doi.org/10.1210/en.2008-0581...
; Qi et al., 2009Qi Y, Oldfield BJ, Clarke IJ. Projections of RFamide-related peptide-3 neurones in the ovine hypothalamus, with special reference to regions regulating energy balance and reproduction. J Neuroendocrinol. 2009;21(8):690-7. http://dx.doi.org/10.1111/j.1365-2826.2009.01886.x. PMid:19500220.
http://dx.doi.org/10.1111/j.1365-2826.20...
; Thorson et al., 2014Thorson JF, Prezotto LD, Cardoso RC, Sharpton SM, Edwards JF, Welsh TH Jr, Riggs AC, Amstalden M, Gary GL. Hypothalamic distribution, adenohypophyseal receptor expression, and ligand functionality of rfamide-related peptide 3 in the mare during the breeding and nonbreeding seasons. Biol Reprod [serial on the Internet]. 2014 Feb 1 [cited 2021 Feb 27];90(2):1-9. Available from: https://academic.oup.com/biolreprod/article-lookup/doi/10.1095/biolreprod.113.112185
https://academic.oup.com/biolreprod/arti...
). The most abundant population of porcine RFRP-ir was observed in the paraventricular nucleus of the hypothalamus (PVN), agreeing with observations in sheep and nonhuman primates (Yano et al., 2003Yano T, Iijima N, Kakihara K, Hinuma S, Tanaka M, Ibata Y. Localization and neuronal response of RFamide related peptides in the rat central nervous system. Brain Res. 2003;982(2):156-67. http://dx.doi.org/10.1016/S0006-8993(03)02877-4. PMid:12915251.
http://dx.doi.org/10.1016/S0006-8993(03)...
; Kriegsfeld 2006Kriegsfeld LJ. Driving reproduction: RFamide peptides behind the wheel. Horm Behav. 2006;50(5):655-66. http://dx.doi.org/10.1016/j.yhbeh.2006.06.004. PMid:16876801.
http://dx.doi.org/10.1016/j.yhbeh.2006.0...
; Smith et al., 2012Smith JT, Young IR, Veldhuis JD, Clarke IJ. Gonadotropin-inhibitory hormone (GnIH) secretion into the ovine hypophyseal portal system. Endocrinology. 2012;153(7):3368-75. http://dx.doi.org/10.1210/en.2012-1088. PMid:22549225.
http://dx.doi.org/10.1210/en.2012-1088...
). In sheep, RFRP fibers project from the PVN to the lateral hypothalamic area, the ARC, and the external zone of the ME, as well as being closely associated with many other neurons, such as GnRH, POMC, NPY, orexin, and Kisspeptin neurons (Smith et al., 2008aSmith JT, Coolen LM, Kriegsfeld LJ, Sari IP, Jaafarzadehshirazi MR, Maltby M, Bateman K, Goodman RL, Tilbrook AJ, Ubuka T, Bentley GE, Clarke IJ, Lehman MN. Variation in Kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology. 2008a;149(11):5770-82. http://dx.doi.org/10.1210/en.2008-0581. PMid:18617612.
http://dx.doi.org/10.1210/en.2008-0581...
, 2012Smith JT, Young IR, Veldhuis JD, Clarke IJ. Gonadotropin-inhibitory hormone (GnIH) secretion into the ovine hypophyseal portal system. Endocrinology. 2012;153(7):3368-75. http://dx.doi.org/10.1210/en.2012-1088. PMid:22549225.
http://dx.doi.org/10.1210/en.2012-1088...
). Moderately dense RFRP fibers were observed in the lateral hypothalamic area of the porcine hypothalamus, but no RFRP fibers were observed in the external zone of the ME of gilts, which would suggest that RFRP is not released into the hypophyseal portal vasculature of the pig as has been observed in sheep (Li et al., 2013Li X, Su J, Fang R, Zheng L, Lei R, Wang X, Lei Z, Jin M, Jiao Y, Hou Y, Guo T, Ma Z. The effects of RFRP-3, the mammalian ortholog of GnIH, on the female pig reproductive axis in vitro. Mol Cell Endocrinol. 2013;372(1-2):65-72. http://dx.doi.org/10.1016/j.mce.2013.03.015. PMid:23541949.
http://dx.doi.org/10.1016/j.mce.2013.03....
).

Early reports indicated that RFRP-3 attenuated GnRH-stimulated gonadotropin synthesis and the release from primary cultures of porcine anterior pituitary cells (Zmijewska et al., 2020Zmijewska A, Czelejewska W, Dziekonski M, Gajewska A, Franczak A, Okrasa S. Effect of kisspeptin and RFamide-related peptide-3 on the synthesis and secretion of LH by pituitary cells of pigs during the estrous cycle. Anim Reprod Sci. 2020;214:106275. http://dx.doi.org/10.1016/j.anireprosci.2020.106275. PMid:32087907.
http://dx.doi.org/10.1016/j.anireprosci....
). Furthermore, GnRH secretion from porcine hypothalamic explants was suppressed upon treatment with RFRP-3 (Li et al., 2013Li X, Su J, Fang R, Zheng L, Lei R, Wang X, Lei Z, Jin M, Jiao Y, Hou Y, Guo T, Ma Z. The effects of RFRP-3, the mammalian ortholog of GnIH, on the female pig reproductive axis in vitro. Mol Cell Endocrinol. 2013;372(1-2):65-72. http://dx.doi.org/10.1016/j.mce.2013.03.015. PMid:23541949.
http://dx.doi.org/10.1016/j.mce.2013.03....
). Additionally, there was a study demonstrated that RFRP-3 inhibits the Kisspeptin-activated GnRH firing rate in vitro, but the addition of RFRP-3 to porcine cultured pituitary cells had no antagonistic effect on the Kisspeptin-induced stimulation of LH secretion (Wu et al., 2009Wu M, Dumalska I, Morozova E, Van Den Pol AN, Alreja M. Gonadotropin inhibitory hormone inhibits basal forebrain vGluT2-gonadotropin-releasing hormone neurons via a direct postsynaptic mechanism. J Physiol. 2009;587(Pt 7):1401-11. http://dx.doi.org/10.1113/jphysiol.2008.166447. PMid:19204051.
http://dx.doi.org/10.1113/jphysiol.2008....
; Zmijewska et al., 2020Zmijewska A, Czelejewska W, Dziekonski M, Gajewska A, Franczak A, Okrasa S. Effect of kisspeptin and RFamide-related peptide-3 on the synthesis and secretion of LH by pituitary cells of pigs during the estrous cycle. Anim Reprod Sci. 2020;214:106275. http://dx.doi.org/10.1016/j.anireprosci.2020.106275. PMid:32087907.
http://dx.doi.org/10.1016/j.anireprosci....
). These results indicate that RFRP-3 may be a negative regulator of pituitary gonadotropin synthesis and release via GnRH neurons. On the contrary, accumulating evidence further showed that central administration of RFRP-3 into the lateral ventricles of the brain within OVX gilts had no effect on the secretory patterns of LH (Thorson et al., 2017Thorson JF, Heidorn NL, Ryu V, Czaja K, Nonneman DJ, Barb CR, Hausman GJ, Rohrer GA, Prezotto LD, McCosh RB, Wright EC, White BR, Freking BA, Oliver WT, Hileman SM, Lents CA. Relationship of neuropeptide FF receptors with pubertal maturation of gilts. Biol Reprod. 2017;96(3):617-34. http://dx.doi.org/10.1095/biolreprod.116.144998. PMid:28339619.
http://dx.doi.org/10.1095/biolreprod.116...
), which is consistent with the effects of RFRP-3 injected into the third ventricle of OVX ewes (Caraty et al., 2012Caraty A, Blomenröhr M, Vogel GMT, Lomet D, Briant C, Beltramo M. RF9 powerfully stimulates gonadotrophin secretion in the Ewe: evidence for a seasonal threshold of sensitivity. J Neuroendocrinol. 2012;24(5):725-36. http://dx.doi.org/10.1111/j.1365-2826.2012.02283.x. PMid:22283564.
http://dx.doi.org/10.1111/j.1365-2826.20...
; Decourt et al., 2016Decourt C, Anger K, Robert V, Lomet D, Bartzen-Sprauer J, Caraty A, Dufourny L, Anderson G, Beltramo M. No Evidence That RFamide-Related Peptide 3 Directly Modulates LH Secretion in the Ewe. Endocrinology. 2016;157(4):1566-75. http://dx.doi.org/10.1210/en.2015-1854. PMid:26862995.
http://dx.doi.org/10.1210/en.2015-1854...
). When RFRP-3 was largely infused into the peripheral circulation of OVX gilts, LH secretion remained unchanged, unless very high doses were given. It also took large pharmacological doses of RFRP-3 to impact the pulsatile secretion of LH in intact mature boars (Thorson et al., 2015Thorson JF, Desaulniers AT, Lee C, White BR, Ford JJ, Lents CA. The role of RFamide-related peptide 3 (RFRP3) in regulation of the neuroendocrine reproductive and growth axes of the boar. Anim Reprod Sci. 2015;159:60-5. http://dx.doi.org/10.1016/j.anireprosci.2015.05.013. PMid:26051609.
http://dx.doi.org/10.1016/j.anireprosci....
). As noted, the porcine RFRP preproprotein can yield an RFRP-2 peptide that ruminants and rodents do not produce (Yoshida et al., 2003Yoshida H, Habata Y, Hosoya M, Kawamata Y, Kitada C, Hinuma S. Molecular properties of endogenous RFamide-related peptide-3 and its interaction with receptors. Biochim Biophys Acta. 2003;1593(2-3):151-7. PMid:12581859.). RFRP-2 is in the same position within the preproprotein as is avian GnIH and the amino acid sequence of porcine RFRP-2 has greater sequence homology with avian GnIH than RFRP-3, so it was speculated that RFRP-2 was a porcine-specific GnIH. However, when OVX gilts received infusions of RFRP-2 into the peripheral circulation, LH pulses were unaffected (Thorson et al., 2017Thorson JF, Heidorn NL, Ryu V, Czaja K, Nonneman DJ, Barb CR, Hausman GJ, Rohrer GA, Prezotto LD, McCosh RB, Wright EC, White BR, Freking BA, Oliver WT, Hileman SM, Lents CA. Relationship of neuropeptide FF receptors with pubertal maturation of gilts. Biol Reprod. 2017;96(3):617-34. http://dx.doi.org/10.1095/biolreprod.116.144998. PMid:28339619.
http://dx.doi.org/10.1095/biolreprod.116...
). Because RFRP does not appear to have a potent suppressive effect on in vivo LH secretion in gilts, either centrally or peripherally, some authors have suggested that RFRP does not appear to act as a hypophysiotropic GnIH in pigs. Interestingly, the influence of RFRP on LH within mammals has been highly inconsistent; for instance, several studies have shown that RFRP-3 can inhibit, have no effect on, or even stimulate LH secretion (Yano et al., 2003Yano T, Iijima N, Kakihara K, Hinuma S, Tanaka M, Ibata Y. Localization and neuronal response of RFamide related peptides in the rat central nervous system. Brain Res. 2003;982(2):156-67. http://dx.doi.org/10.1016/S0006-8993(03)02877-4. PMid:12915251.
http://dx.doi.org/10.1016/S0006-8993(03)...
; Murakami et al., 2008Murakami M, Matsuzaki T, Iwasa T, Yasui T, Irahara M, Osugi T, Tsutsui K. Hypophysiotropic role of RFamide-related peptide-3 in the inhibition of LH secretion in female rats. J Endocrinol. 2008;199(1):105-12. http://dx.doi.org/10.1677/JOE-08-0197. PMid:18653621.
http://dx.doi.org/10.1677/JOE-08-0197...
; Anderson et al., 2009Anderson GM, Relf H-L, Rizwan MZ, Evans JJ. Central and peripheral effects of RFamide-Related Peptide-3 on luteinizing hormone and prolactin secretion in rats. Endocrinology. 2009;150(4):1834-40. http://dx.doi.org/10.1210/en.2008-1359. PMid:19022888.
http://dx.doi.org/10.1210/en.2008-1359...
; Rizwan et al., 2009Rizwan MZ, Porteous R, Herbison AE, Anderson GM. Cells expressing RFamide-related peptide-1/3, the mammalian gonadotropin-inhibitory hormone orthologs, are not hypophysiotropic neuroendocrine neurons in the rat. Endocrinology. 2009;150(3):1413-20. http://dx.doi.org/10.1210/en.2008-1287. PMid:19008316.
http://dx.doi.org/10.1210/en.2008-1287...
; Pineda et al., 2010Pineda R, Garcia-Galiano D, Sanchez-Garrido MA, Romero M, Ruiz-Pino F, Aguilar E, Dijcks FA, Blomenröhr M, Pinilla L, van Noort PI, Tena-Sempere M. Characterization of the inhibitory roles of RFRP3, the mammalian ortholog of GnIH, in the control of gonadotropin secretion in the rat: in vivo and in vitro studies. Am J Physiol Endocrinol Metab. 2010;299(1):E39-46. http://dx.doi.org/10.1152/ajpendo.00108.2010. PMid:20424142.
http://dx.doi.org/10.1152/ajpendo.00108....
). It therefore remains unclear what role RFRP plays in porcine reproduction, requiring further research and analysis for pigs.

Endogenous opioid peptides (EOP)

Endogenous opioid peptides (EOP) consist collectively of endorphins, enkephalins, and dynorphins, playing important roles in suppressing LH secretion in luteal phase gilts and lactating sows. Immunocytochemical studies in gilts demonstrated the existence of pro-opiomelanocortin (POMC) perikarya in the ARC with fibers projecting to the MBH, PeV, ME, and preoptic area (Weems et al., 2018Weems PW, Lehman MN, Coolen LM, Goodman RL. The roles of neurokinins and endogenous opioid peptides in control of pulsatile LH secretion. In: Litwack G, editor. Vitamins and hormones [Internet]. USA: Elsevier; 2018 [cited 2021 Feb 27]. p. 89-135. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0083672918300116
https://linkinghub.elsevier.com/retrieve...
). Following intracerebroventricular (ICV) treatment with morphine, an EOP agonist, decreased secretion of LH, and FSH in prepubertal OVX gilts. In contrast, the general opioid receptor antagonist, naloxone, increased LH release in prepubertal gilts. Naloxone stimulated GnRH secretion from the hypothalamic-preoptic area collected from gilts, indicating that the EOP may inhibit LH secretion by action at the central nervous system. Moreover, naloxone failed to increase LH release in boars given antisera against GnRH. An adenohypophysial site of action in modulating LH release is supported by in vitro studies in which β-endorphin decreased basal and GnRH-induced LH secretion by porcine pituitary cells. In contrast, exposure to naloxone increased basal secretion of LH and enhanced pituitary responsiveness to GnRH (Wylot et al., 2013Wylot B, Tworus K, Okrasa S. the effects of mu-, delta- and kappa-opioid receptor activation on luteinizing and follicle-stimulating hormone secretion from porcine pituitary cells. J Physiol Pharmacol. 2013;64(4):505-11. PMid:24101398.).

Neuropeptide Y (NPY)

Neuropeptide Y (NPY) is a 36-amino-acid tyrosine-rich peptide that was first isolated from porcine brain extracts in 1982 and belongs to the “NPY family” of biologically active peptides. It includes two gut hormones: peptide YY (PYY) and pancreatic polypeptide (PP). NPY affects target cells by activating various G-coupled receptors belonging to the rhodopsin-like superfamily of receptors (Siawrys and Buchowski, 2018Siawrys G, Buchowski H. Modulation of anterior pituitary cell luteinizing hormone secretory activity by neuropeptide Y in early pregnant pigs. J Physiol Pharmacol. 2018;69(5):719-26. https://doi.org/10.26402/jpp.2018.5.06.
https://doi.org/10.26402/jpp.2018.5.06...
). Additionally, NPY as an orexigenic peptide is simultaneously involved in the modulation of the GnRH/LH system and could provide a link between nutrition and reproduction. In the pig, NPY receptors are widely distributed in the structures of the central nervous system and innervating peripheral organs, with a predominant localization in stalk-median eminence (SME), POA, MBH, and the pituitary (Óvilo et al., 2010Óvilo C, Fernández A, Fernández AI, Folch JM, Varona L, Benítez R, Nuñez Y, Rodríguez C, Silió L. Hypothalamic expression of porcine leptin receptor (LEPR), neuropeptide Y (NPY), and cocaine- and amphetamine-regulated transcript (CART) genes is influenced by LEPR genotype. Mamm Genome. 2010;21(11–12):583-91. http://dx.doi.org/10.1007/s00335-010-9307-1. PMid:21128076.
http://dx.doi.org/10.1007/s00335-010-930...
). NPY is widespread in the porcine CNS, including the limbic system, olfactory system, hypothalamoneurohypophysial tract, corpus striatum, and cerebral cortex. Barb revealed that the central administration of NPY suppresses serum LH concentrations and LH pulse frequency in OVX prepubertal gilts (Barb et al., 2006Barb CR, Kraeling RR, Rampacek GB, Hausman GJ. The role of neuropeptide Y and interaction with leptin in regulating feed intake and luteinizing hormone and growth hormone secretion in the pig. Reproduction. 2006;131(6):1127-35. http://dx.doi.org/10.1530/rep.1.01108. PMid:16735552.
http://dx.doi.org/10.1530/rep.1.01108...
). Generally, based on studies performed with different species, there are many reports indicating that NPY may regulate LH secretion at the hypothalamic level by directly and/or indirectly modulating the activity of the GnRH neuronal system (Wójcik-Gładysz and Polkowska 2006Wójcik-Gładysz A, Polkowska J. Neuropeptide Y--a neuromodulatory link between nutrition and reproduction at the central nervous system level. Reprod Biol. 2006;6(Suppl. 2):21-8. PMid:17220938.; Dhillon et al., 2009Dhillon SS, Gingerich S, Belsham DD. Neuropeptide Y induces gonadotropin-releasing hormone gene expression directly and through conditioned medium from mHypoE-38 NPY neurons. Regul Pept. 2009;156(1-3):96-103. http://dx.doi.org/10.1016/j.regpep.2009.04.005. PMid:19371763.
http://dx.doi.org/10.1016/j.regpep.2009....
; Roa and Herbison 2012Roa J, Herbison AE. Direct regulation of gnrh neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology. 2012;153(11):5587-99. http://dx.doi.org/10.1210/en.2012-1470. PMid:22948210.
http://dx.doi.org/10.1210/en.2012-1470...
; Amstalden et al., 2014Amstalden M, Cardoso RC, Alves BRC, Williams GL. Reproduction Symposium: hypothalamic neuropeptides and the nutritional programming of puberty in heifers1,2. J Anim Sci. 2014;92(8):3211-22. http://dx.doi.org/10.2527/jas.2014-7808. PMid:24894003.
http://dx.doi.org/10.2527/jas.2014-7808...
). Moreover, morphological studies have proved that NPY neurons come in close contact with GnRH neurons in POA, ARC, and ME (Klenke et al., 2010Klenke U, Constantin S, Wray S. Directly Inhibits neuronal activity in a subpopulation of gonadotropin-releasing hormone-1 neurons via Y1 receptors. Endocrinology. 2010;151(6):2736-46. http://dx.doi.org/10.1210/en.2009-1198. PMid:20351316.
http://dx.doi.org/10.1210/en.2009-1198...
). It is expected that NPY suppresses LH pulse frequency by inhibiting both GnRH and Kisspeptin cells in the gilt hypothalamus, but this problem requires further and more detailed investigation, including on the use of specific agonists and/or antagonists of all NPY receptor subtypes.

Galanin (GAL)

Galanin (GAL) is a brain-gut neuropeptide widely distributed in the POA, MBH, and pituitary stalk-median eminence of the cyclic gilt (Czujkowska and Arciszewski 2016Czujkowska A, Arciszewski MB. Galanin is Co-Expressed with Substance P, Calbindin and Corticotropin-Releasing Factor (CRF) in The Enteric Nervous System of the Wild Boar (Sus scrofa) Small Intestine. Anat Histol Embryol. 2016;45(2):115-23. http://dx.doi.org/10.1111/ahe.12179. PMid:25907507.
http://dx.doi.org/10.1111/ahe.12179...
). The anorexigenic neuropeptide GAL expression and immunoreactivity are regulated by Estrogen (Spergel 2019Spergel DJ. Neuropeptidergic modulation of GnRH neuronal activity and GnRH secretion controlling reproduction: insights from recent mouse studies. Cell Tissue Res. 2019;375(1):179-91. http://dx.doi.org/10.1007/s00441-018-2893-z. PMid:30078104.
http://dx.doi.org/10.1007/s00441-018-289...
). GAL is likely co-released with Kisspeptin from subsets of Kisspeptin neuron axons onto GnRH neurons and both the GALR1 and GALR2 subtypes of GAL receptor appear to be expressed in GnRH neurons (Constantin and Wray 2016Constantin S, Wray S. Galanin activates G protein gated inwardly rectifying potassium channels and suppresses Kisspeptin-10 activation of GnRH neurons. Endocrinology. 2016;157(8):3197-212. http://dx.doi.org/10.1210/en.2016-1064. PMid:27359210.
http://dx.doi.org/10.1210/en.2016-1064...
). GAL stimulated basal but not GnRH-induced LH secretion from porcine pituitary glands in vitro and antiserum to galanin suppressed GnRH-induced LH release (Elsaesser 2001Elsaesser F. Stimulation of porcine pituitary luteinizing hormone release by galanin: putative auto/paracrine regulation. Neuroendocrinology. 2001;74(5):288-99. http://dx.doi.org/10.1159/000054696. PMid:11694761.
http://dx.doi.org/10.1159/000054696...
).

Neuropeptides that may or may not act directly on GnRH neurons

Neurokinin B (NKB)

Inactivating mutations in genes encoding neurokinin B (NKB) or its receptor NK3R results in hypogonadotropic hypogonadism and failure to attain puberty in rodents and humans, a phenotype reminiscent of that of patients with mutations of Kiss1 or GPR54 (de Roux et al., 2003de Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA. 2003;100(19):10972-6. http://dx.doi.org/10.1073/pnas.1834399100. PMid:12944565.
http://dx.doi.org/10.1073/pnas.183439910...
; Topaloglu et al., 2009Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O’Rahilly S, Semple RK. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet. 2009;41(3):354-8. http://dx.doi.org/10.1038/ng.306. PMid:19079066.
http://dx.doi.org/10.1038/ng.306...
). In addition, initial studies in mice and sheep, later confirmed in other species, found that the Kisspeptin neurons in the ARC co-express neurokinin B (NKB), also known as tachykinin 3 (TAC3), which acts through its homologous receptor (TAC3R) (Burke et al., 2006Burke MC, Letts PA, Krajewski SJ, Rance NE. Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: morphologic evidence of interrelated function within the arcuate nucleus. J Comp Neurol. 2006;498(5):712-26. http://dx.doi.org/10.1002/cne.21086. PMID: 16917850.
http://dx.doi.org/10.1002/cne.21086...
; Goodman et al., 2007Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CVR, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, Clarke IJ. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology. 2007;148(12):5752-60. http://dx.doi.org/10.1210/en.2007-0961. PMid:17823266.
http://dx.doi.org/10.1210/en.2007-0961...
; Navarro et al., 2009Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of Gonadotropin-Releasing Hormone Secretion by Kisspeptin/Dynorphin/Neurokinin B Neurons in the Arcuate Nucleus of the Mouse. J Neurosci. 2009;29(38):11859-66. http://dx.doi.org/10.1523/JNEUROSCI.1569-09.2009. PMid:19776272.
http://dx.doi.org/10.1523/JNEUROSCI.1569...
). Similarly, studies in pig ARC have shown that virtually all Kisspeptin neurons in co-express NKB (Lents et al., 2020Lents CA, Lindo AN, Hileman SM, Nonneman DJ. Physiological and genomic insight into neuroendocrine regulation of puberty in gilts. Domest Anim Endocrinol. 2020;73:106446. http://dx.doi.org/10.1016/j.domaniend.2020.106446. PMid:32199704.
http://dx.doi.org/10.1016/j.domaniend.20...
). Because the roles of NKB and its receptor in regulating GnRH of the pig are not presently understood, the expression of TAC3R has recently been localized throughout several areas of the hypothalamus in ovariectomized (OVX) gilts (Lindo 2018Lindo A. Characterization of KNDy neuronal activity in gilts: distribution and effect of a progestin [thesis]. Morgantown: West Virginia University; 2018.). Many of the hypothalamic regions that display TAC3R immunostaining in the pig also contain GnRH neurons. Furthermore, the greatest number of TAC3R expressing cells are the dbB and the PVN, followed by the POA and SCN. The PeV and RCh have evidence of TAC3R immunostaining (Lindo 2018Lindo A. Characterization of KNDy neuronal activity in gilts: distribution and effect of a progestin [thesis]. Morgantown: West Virginia University; 2018.). Although about 40% of GnRH neurons occurred in close apposition to TAC3R containing cells, close contacts were few, suggesting that the TAC3R containing cells in the porcine hypothalamus do not directly regulate GnRH neurons in pigs.

It is postulated from molecular, anatomical, and physiological data that NKB acts as an autoregulatory signal for Kisspeptin-neurokin B-dynorphin (KNDy) neurons, stimulating Kisspeptin output to GnRH neurons. The fact that NKB operates via Kisspeptin signaling to modulate GnRH neurons is supported by a wealth of data, including the demonstration that within monkeys the desensitization of TAC3R blocks the effect of senktide (an NKB agonist) on gonadotropin release, and the fact that ICV injection of senktide into rodents induces c-Fos in ARC Kiss1 neurons, which express NK3R and are excited by NKB (Navarro et al., 2009Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of Gonadotropin-Releasing Hormone Secretion by Kisspeptin/Dynorphin/Neurokinin B Neurons in the Arcuate Nucleus of the Mouse. J Neurosci. 2009;29(38):11859-66. http://dx.doi.org/10.1523/JNEUROSCI.1569-09.2009. PMid:19776272.
http://dx.doi.org/10.1523/JNEUROSCI.1569...
, 2011Navarro VM, Castellano JM, McConkey SM, Pineda R, Ruiz-Pino F, Pinilla L, Clifton DK, Tena-Sempere M, Steiner RA. Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat. Am J Physiol Endocrinol Metab. 2011;300(1):E202-10. http://dx.doi.org/10.1152/ajpendo.00517.2010. PMid:21045176.
http://dx.doi.org/10.1152/ajpendo.00517....
; Ramaswamy et al., 2011Ramaswamy S, Seminara SB, Plant TM. Evidence from the agonadal juvenile male rhesus monkey (Macaca mulatta) for the view that the action of neurokinin B to Trigger Gonadotropin-Releasing Hormone Release Is Upstream from the Kisspeptin Receptor. Neuroendocrinology. 2011;94(3):237-45. http://dx.doi.org/10.1159/000329045. PMid:21832818.
http://dx.doi.org/10.1159/000329045...
). Moreover, the effect of senktide is absent in GPR54 null mice but is preserved in mice engineered to maintain Kisspeptin actions only in GnRH neurons, attesting that NKB signaling is upstream of Kisspeptin in the control of GnRH neurons (de Croft et al., 2013de Croft S, Boehm U, Herbison AE. Activates arcuate kisspeptin neurons through multiple tachykinin receptors in the male mouse. Endocrinology. 2013;154(8):2750-60. http://dx.doi.org/10.1210/en.2013-1231. PMid:23744641.
http://dx.doi.org/10.1210/en.2013-1231...
). There is little published data on NKB in pigs, but the spatial distribution of NKB expression within the porcine hypothalamus has inferred the function of NKB on GnRH neurons as well. Furthermore, some studies in the gilt suggested that the amplitude of LH pulses may be regulated by NKB, and the pubertal decrease in sensitivity to oestrogen negative feedback in the gilt involves the gene expression for TAC3 and the TAC3R gene in the medial basal hypothalamus (MBH) (Thorson et al., 2018Thorson JF, Prezotto LD, Adams H, Petersen SL, Clapper JA, Wright EC, Oliver WT, Freking BA, Foote AP, Berry ED, Nonneman DJ, Lents CA. Energy balance affects pulsatile secretion of luteinizing hormone from the adenohypophesis and expression of neurokinin B in the hypothalamus of ovariectomized gilts†. Biol Reprod. 2018;99(2):433-45. http://dx.doi.org/10.1093/biolre/ioy069. PMid:30101293.
http://dx.doi.org/10.1093/biolre/ioy069...
). Thus, it is likely that NKB in pigs acts through an autoregulatory mechanism involving TAC3R to induce the release of Kisspeptin, which acts directly on the GnRH neuronal network to stimulate a pulsatile release of GnRH and subsequently LH.

Neuromedin B (NMB)

Neuromedin B (NMB) is a member of a family of bombesin-like peptides in mammals, which are decapeptides originally identified in porcine spinal cords (Jensen et al., 2008Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States. Pharmacol Rev. 2008;60(1):1-42. http://dx.doi.org/10.1124/pr.107.07108. PMid:18055507.
http://dx.doi.org/10.1124/pr.107.07108...
). Amino acid sequences from sequenced cDNA show that the Neuromedin B receptor (NMBR) in pigs is typical of the G protein-coupled receptor (GPCR) family, serving as a 390-amino acid protein with seven membrane spanning domains (Ohki-Hamazaki et al., 2005Ohki-Hamazaki H, Iwabuchi M, Maekawa F. Development and function of bombesin-like peptides and their receptors. Int J Dev Biol. 2005;49(2-3):293-300. http://dx.doi.org/10.1387/ijdb.041954ho. PMid:15906244.
http://dx.doi.org/10.1387/ijdb.041954ho...
). NMB/NMBR is an important physiological regulator of smooth muscle contraction, via activation of intracellular signaling pathways. The expression of NMB mRNA in the central nervous system (CNS) as well the presence of NMBR mRNA and protein in the pituitary, testis, ovaries, and uterus, suggest the potential physiological functions of the NMB/NMBR system during reproduction in pigs (Ma et al., 2016Ma Z, Su J, Guo T, Jin M, Li X, Lei Z, Hou Y, Li X, Jia C, Zhang Z, Ahmed E. Neuromedin B and its receptor: gene cloning, tissue distribution and expression levels of the reproductive axis in pigs. PLoS ONE. 2016 Mar 24;11(3):e0151871. https://doi.org/10.1371/journal.pone.0151871.
https://doi.org/10.1371/journal.pone.015...
). Moreover, the expression patterns of NMB and NMBR mRNA along the reproductive axis for female pigs across the estrous cycle and for male pigs at postnatal development stages, support the suggestion that NMB may control the release of GnRH through the regulation of NMBR secretion (Ma et al., 2018Ma Z, Zhang Y, Su J, Yang S, Qiao W, Li X, Lei Z, Cheng L, An N, Wang W, Feng Y, Zhang J. Effects of neuromedin B on steroidogenesis, cell proliferation and apoptosis in porcine Leydig cells. J Mol Endocrinol. 2018;61(1):13-23. http://dx.doi.org/10.1530/JME-17-0242. PMid:29632025.
http://dx.doi.org/10.1530/JME-17-0242...
). It has previously been shown that NMB can stimulate the HPG axis via hypothalamic GnRH in male rats (Boughton et al., 2013Boughton CK, Patel SA, Thompson EL, Patterson M, Curtis AE, Amin A, Chen K, Ghatei MA, Bloom SR, Murphy KG. Neuromedin B stimulates the hypothalamic–pituitary–gonadal axis in male rats. Regul Pept. 2013;187:6-11. http://dx.doi.org/10.1016/j.regpep.2013.10.002. PMid:24120470.
http://dx.doi.org/10.1016/j.regpep.2013....
). However, the mechanism and physiological function of the NMB/NMBR system on porcine reproduction are currently not fully understood, requiring further research and analysis.

Neuromedin S (NMS)

Neuromedin S (NMS) has been reported to have many physiological functions in mammals and has been identified as an endogenous ligand for two orphan G protein-coupled receptors, FM-3/GPR66 (NMU1R) and FM-4/TGR-1 (NMU2R)(Roesler et al., 2012Roesler R, Kent P, Schröder N, Schwartsmann G, Merali Z. Bombesin receptor regulation of emotional memory. Rev Neurosci. 2012;23(5–6):571-86. PMid:23096238.). The distribution and location of NMS have mainly been identified in the pig’s hypothalamic region, including in the periventricular nucleus (PEN), PVN, SCN, supraoptic nucleus (SON), VMH, and ARC (Mori et al., 2005Mori K, Miyazato M, Ida T, Murakami N, Serino R, Ueta Y, Kojima M, Kangawa K. Identification of neuromedin S and its possible role in the mammalian circadian oscillator system. EMBO J. 2005;24(2):325-35. http://dx.doi.org/10.1038/sj.emboj.7600526. PMid:15635449.
http://dx.doi.org/10.1038/sj.emboj.76005...
). NMU2R is widely distributed in male pig hypothalamic cells, anterior pituitary cells, and Leydig cells, suggesting that the NMS/NMU2R system existed in the male pig reproductive axis and may play a significant role in the regulation of gonadotropin secretion in the brain and testis, which was similar to its function in other mammals (Yang et al., 2012Yang G, Su J, Yao Y, Lei Z, Zhang G, Liu Y, Liu J, Li X. Distribution of neuromedin S and its receptor NMU2R in pigs. Res Vet Sci. 2012;92(2):180-6. http://dx.doi.org/10.1016/j.rvsc.2010.11.013. PMid:21185043.
http://dx.doi.org/10.1016/j.rvsc.2010.11...
; Ma et al., 2017Ma Z, Zhao Y, Yao Y, Lei Z, Jin M, Li X, Jia C, Zhang Z, Li X, Su J. Postnatal developmental of Neuromedin S and its receptor in the male Xiaomeishan pig reproductive axis. Anim Reprod Sci. 2017;181:115-24. http://dx.doi.org/10.1016/j.anireprosci.2017.03.023. PMid:28389048.
http://dx.doi.org/10.1016/j.anireprosci....
). At present, evidence has revealed that NMS increases the release of LH and FSH from anterior pituitary cells and testosterone from Leydig cells as well as the expression of NMU2R and GnRH mRNAs in hypothalamic cells, NMU2R, LH, and FSH mRNAs in anterior pituitary cells; moreover, it downregulated the expression of GnIH mRNA in hypothalamic cells (Jin et al., 2019Jin M, Ma Z, Li X, Su J, Lei Z. The effects of neuromedin S on the hypothalamic-pituitary-testicular axis in male pigs in vitro. Gen Comp Endocrinol. 2019;280:73-81. http://dx.doi.org/10.1016/j.ygcen.2019.04.013. PMid:30981702.
http://dx.doi.org/10.1016/j.ygcen.2019.0...
). Interestingly, lateral ventricle injection of NMS could significantly decrease LH response including serum LH level and LH mRNA expression in ovariectomized pigs, which is partially consistent with the previous results on rats (Yang et al., 2010Yang G, Su J, Yao Y, Lei Z, Zhang G, Li X. The regulatory mechanism of neuromedin S on luteinizing hormone in pigs. Anim Reprod Sci. 2010;122(3–4):367-74. http://dx.doi.org/10.1016/j.anireprosci.2010.10.011. PMid:21071159.
http://dx.doi.org/10.1016/j.anireprosci....
). The inhibitory effect of NMS on LH contradicts previous reports of a positive role of NMS on the reproductive axis in vitro, but these results indicated that NMS may play an important role in the regulation of reproductive function via the NMU2R or GnRH.

Nesfatin-1

The hypothalamic peptide, Nesfatin-1, derived from the precursor NEFA/nucleobindin 2 (NUCB2), was identified as anorexigenic signal, acting in a leptin-independent manner (Garcia-Galiano et al., 2010Garcia-Galiano D, Navarro VM, Roa J, Ruiz-Pino F, Sanchez-Garrido MA, Pineda R, Castellano JM, Romero M, Aguilar E, Gaytán F, Diéguez C, Pinilla L, Tena-Sempere M. The anorexigenic neuropeptide, Nesfatin-1, Is indispensable for normal puberty onset in the female rat. J Neurosci. 2010;30(23):7783-92. http://dx.doi.org/10.1523/JNEUROSCI.5828-09.2010. PMid:20534827.
http://dx.doi.org/10.1523/JNEUROSCI.5828...
). Nesfatin-1 is expressed in the ventrolateral medulla (VLM), dorsal vagal complex (DVC), PVN, ARC, and SON of the pig brain (Gaigé et al., 2013Gaigé S, Bonnet MS, Tardivel C, Pinton P, Trouslard J, Jean A, Guzylack L, Troadec JD, Dallaporta M. c-Fos immunoreactivity in the pig brain following deoxynivalenol intoxication: focus on NUCB2/nesfatin-1 expressing neurons. Neurotoxicology. 2013;34:135-49. http://dx.doi.org/10.1016/j.neuro.2012.10.020. PMid:23164930.
http://dx.doi.org/10.1016/j.neuro.2012.1...
). Accumulating evidence indicated that Nesfatin-1 regulates glucose metabolism, insulin secretion, gastrointestinal motility, stress response, development, cardiovascular functions, anxiety, and the onset of puberty (Aydin, 2013Aydin S. Multi-functional peptide hormone NUCB2/nesfatin-1. Endocrine. 2013;44(2):312-25. http://dx.doi.org/10.1007/s12020-013-9923-0. PMid:23526235.
http://dx.doi.org/10.1007/s12020-013-992...
). Nesfatin-1 stimulates the secretion of GnRH and LHβ in vitro, raising the possibility of Nesfatin-1 acting directly on hypothalamic neurons and gonadotropes (Kalló et al., 2012Kalló I, Vida B, Deli L, Molnár CS, Hrabovszky E, Caraty A, Ciofi P, Coen CW, Liposits Z. Co-localisation of kisspeptin with galanin or neurokinin B in afferents to mouse GnRH neurones. J Neuroendocrinol. 2012;24(3):464-76. http://dx.doi.org/10.1111/j.1365-2826.2011.02262.x. PMid:22129075.
http://dx.doi.org/10.1111/j.1365-2826.20...
).

Phoenixin (PNX)

Phoenixin (PNX) is a recently discovered hypothalamic neuropeptide, first identified in 2013 (Yosten et al., 2013Yosten GLC, Lyu R-M, Hsueh AJW, Avsian-Kretchmer O, Chang J-K, Tullock CW, Dun SL, Dun N, Samson WK. A novel reproductive peptide, phoenixin. J Neuroendocrinol. 2013;25(2):206-15. http://dx.doi.org/10.1111/j.1365-2826.2012.02381.x. PMid:22963497.
http://dx.doi.org/10.1111/j.1365-2826.20...
). Phoenixin acts through its receptor, G protein-coupled receptor 173 (GPR173), to activate the cAMP/PKA pathway resulting in the phosphorylation of CREB (pCREB) (Treen et al., 2016Treen AK, Luo V, Belsham DD. Phoenixin activates immortalized GnRH and kisspeptin neurons through the novel receptor GPR173. Mol Endocrinol. 2016;30(8):872-88. http://dx.doi.org/10.1210/me.2016-1039. PMid:27268078.
http://dx.doi.org/10.1210/me.2016-1039...
). PXN potentiates GnRH-stimulated LH release and increases GnRH and KISS1 gene expression, respectively, and it also raises the expression of GnRH receptor gene (Clarke and Dhillo, 2019Clarke SA, Dhillo WS. Phoenixin and its role in reproductive hormone release. Semin Reprod Med. 2019;27(4):191-6. http://dx.doi.org/10.1055/s-0039-3400964. PMid:31972864.
http://dx.doi.org/10.1055/s-0039-3400964...
). Alternatively, compromise of PXN in vivo using siRNA led to a reduction in GnRH receptor expression in the pituitary and the delayed appearance of oestrus (Nguyen et al., 2019Nguyen XP, Nakamura T, Osuka S, Bayasula B, Nakanishi N, Kasahara Y, Muraoka A, Hayashi S, Nagai T, Murase T, Goto M, Iwase A, Kikkawa F. Effect of the neuropeptide phoenixin and its receptor GPR173 during folliculogenesis. Reproduction. 2019;158(1):25-34. http://dx.doi.org/10.1530/REP-19-0025. PMid:30933929.
http://dx.doi.org/10.1530/REP-19-0025...
). Until now, it is expected that PNX may have important roles in the regulation of porcine reproductive function, yet to be delineated (Lepiarczyk et al., 2020Lepiarczyk E, Bossowska A, Majewska M, Skowrońska A, Kaleczyc J, Majewski M. Distribution and chemical coding of phoenixin-immunoreactive nerve structures in the spinal cord of the pig. Ann Anat. 2020;232:151559. http://dx.doi.org/10.1016/j.aanat.2020.151559. PMid:32569824.
http://dx.doi.org/10.1016/j.aanat.2020.1...
).

Conclusion

In this review, beginning from the anatomic distribution and pharmacological function of neuropeptides, we follow the neuroendocrine pathways and mechanisms that control reproduction in pigs. GnRH neurons play a particularly critical role in the function of the reproductive central nervous system and act as the intermediate factor between the hypothalamus and hypophysis. The activity of GnRH neurons is regulated by different neuropeptides, forming a central control network. Kisspeptin neurons along with neurokinin B in the POA regulate GnRH cell bodies and in the ARC act on GnRH terminal axons in the median eminence, which is essential for GnRH neurons to stimulate LH secretion in pigs. Rather, it is speculated that RFRPs act as the essential upstream regulators in the control of GnRH secretion with an inhibitory effect in pigs, as has been proposed for rats and nonhuman primates, but remains unclear. NPY and POMC cells function as metabolic sensors for the activation of GnRH secretion, acting as inhibitory and excitatory signals, respectively. Additionally, EOP inhibition of GnRH secretion in pigs involves the direct suppression of noradrenergic neurons, which may come about with increasing sexual maturity. Several neuropeptides may play an important role in the regulation of reproductive functions via hypothalamic GnRH, such as NMB, NMS, PNX, GAL, Nesfatin-1, and as such, require further research and analysis (Figure 1).

Figure 1
Schematic illustration of the reproductive neuroendocrine pathways in pigs. The reproduction of pigs is operated by the HPG axis, in which GnRH neurons act as the intermediate factor between the hypothalamus and hypophysis. GnRH neurons directly or indirectly receive regulatory inputs from a wide array of regulatory signals and pathways, involving numerous neuropeptides and neurotransmitters. Kisspeptin neurons with neurokinin B in the POA regulate GnRH cell bodies and in the ARC act on GnRH terminal axons in the median eminence, stimulating GnRH secretion. NPY and POMC cells function as metabolic sensors for the activation of GnRH secretion, acting as inhibitory and excitatory signals, respectively. Rather, it is speculated that RFRP-3, NMB, NMS, PNX, GAL, and Nesfatin-1 act as the essential upstream regulators in the control of GnRH secretion, but remains unclear.

The list of neuropeptides known to modulate or potentially modulate GnRH neuronal activity and GnRH secretion in gilts will likely grow as the effects on GnRH neurons of additional neuropeptides, including those of neuropeptides that are yet to be discovered, are investigated. Although it is clear, based mostly on pharmacological and immunohistochemical studies, that some of the neuropeptides investigated thus far impact directly GnRH neurons and the receptors to which they bind on GnRH neurons, further research is required to understand their signaling mechanisms in GnRH neurons and to determine whether other known and yet undiscovered neuropeptides affect GnRH neurons directly or indirectly.

Acknowledgements

The authors thank to Prof. Pingqing Wang for his valuable advice of the manuscript.

  • Financial support: Fundamental Research Funds for the Key Research Program of Chongqing Science and Technology Commission (Grant No. cstc2019jscx-gksbX0099) and National Key R&D Program of China (Grant No. 2017YFD0501902).

References

  • Amstalden M, Cardoso RC, Alves BRC, Williams GL. Reproduction Symposium: hypothalamic neuropeptides and the nutritional programming of puberty in heifers1,2. J Anim Sci. 2014;92(8):3211-22. http://dx.doi.org/10.2527/jas.2014-7808 PMid:24894003.
    » http://dx.doi.org/10.2527/jas.2014-7808
  • Ancel C, Bentsen AH, Sébert M-E, Tena-Sempere M, Mikkelsen JD, Simonneaux V. Stimulatory effect of RFRP-3 on the gonadotrophic axis in the male syrian hamster: the exception proves the rule. Endocrinology. 2012;153(3):1352-63. http://dx.doi.org/10.1210/en.2011-1622 PMid:22275511.
    » http://dx.doi.org/10.1210/en.2011-1622
  • Anderson GM, Relf H-L, Rizwan MZ, Evans JJ. Central and peripheral effects of RFamide-Related Peptide-3 on luteinizing hormone and prolactin secretion in rats. Endocrinology. 2009;150(4):1834-40. http://dx.doi.org/10.1210/en.2008-1359 PMid:19022888.
    » http://dx.doi.org/10.1210/en.2008-1359
  • Arreguin-Arevalo JA, Lents CA, Farmerie TA, Nett TM, Clay CM. KiSS-1 peptide induces release of LH by a direct effect on the hypothalamus of ovariectomized ewes. Anim Reprod Sci. 2007;101(3-4):265-75. http://dx.doi.org/10.1016/j.anireprosci.2006.09.021 PMid:17055196.
    » http://dx.doi.org/10.1016/j.anireprosci.2006.09.021
  • Aydin S. Multi-functional peptide hormone NUCB2/nesfatin-1. Endocrine. 2013;44(2):312-25. http://dx.doi.org/10.1007/s12020-013-9923-0 PMid:23526235.
    » http://dx.doi.org/10.1007/s12020-013-9923-0
  • Barb CR, Robertson AS, Barrett JB, Kraeling RR, Houseknecht KL. The role of melanocortin-3 and -4 receptor in regulating appetite, energy homeostasis and neuroendocrine function in the pig. J Endocrinol. 2004;181(1):39-52. http://dx.doi.org/10.1677/joe.0.1810039 PMid:15072565.
    » http://dx.doi.org/10.1677/joe.0.1810039
  • Barb CR, Kraeling RR, Rampacek GB, Hausman GJ. The role of neuropeptide Y and interaction with leptin in regulating feed intake and luteinizing hormone and growth hormone secretion in the pig. Reproduction. 2006;131(6):1127-35. http://dx.doi.org/10.1530/rep.1.01108 PMid:16735552.
    » http://dx.doi.org/10.1530/rep.1.01108
  • Barb CR, Hausman GJ, Rekaya R, Lents CA, Lkhagvadorj S, Qu L, Cai W, Couture OP, Anderson LL, Dekkers JC, Tuggle CK. Gene expression in hypothalamus, liver, and adipose tissues and food intake response to melanocortin-4 receptor agonist in pigs expressing melanocortin-4 receptor mutations. Physiol Genomics. 2010;41(3):254-68. http://dx.doi.org/10.1152/physiolgenomics.00006.2010 PMid:20215418.
    » http://dx.doi.org/10.1152/physiolgenomics.00006.2010
  • Bentley GE, Tsutsui K, Kriegsfeld LJ. Recent studies of gonadotropin-inhibitory hormone (GnIH) in the mammalian hypothalamus, pituitary and gonads. Brain Res. 2010;1364:62-71. http://dx.doi.org/10.1016/j.brainres.2010.10.001 PMid:20934414.
    » http://dx.doi.org/10.1016/j.brainres.2010.10.001
  • Boughton CK, Patel SA, Thompson EL, Patterson M, Curtis AE, Amin A, Chen K, Ghatei MA, Bloom SR, Murphy KG. Neuromedin B stimulates the hypothalamic–pituitary–gonadal axis in male rats. Regul Pept. 2013;187:6-11. http://dx.doi.org/10.1016/j.regpep.2013.10.002 PMid:24120470.
    » http://dx.doi.org/10.1016/j.regpep.2013.10.002
  • Burke MC, Letts PA, Krajewski SJ, Rance NE. Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: morphologic evidence of interrelated function within the arcuate nucleus. J Comp Neurol. 2006;498(5):712-26. http://dx.doi.org/10.1002/cne.21086 PMID: 16917850.
    » http://dx.doi.org/10.1002/cne.21086
  • Caraty A, Smith JT, Lomet D, Ben Saïd S, Morrissey A, Cognie J, Doughton B, Baril G, Briant C, Clarke IJ. Kisspeptin Synchronizes Preovulatory Surges in Cyclical Ewes and Causes Ovulation in Seasonally Acyclic Ewes. Endocrinology. 2007;148(11):5258-67. http://dx.doi.org/10.1210/en.2007-0554 PMid:17702853.
    » http://dx.doi.org/10.1210/en.2007-0554
  • Caraty A, Blomenröhr M, Vogel GMT, Lomet D, Briant C, Beltramo M. RF9 powerfully stimulates gonadotrophin secretion in the Ewe: evidence for a seasonal threshold of sensitivity. J Neuroendocrinol. 2012;24(5):725-36. http://dx.doi.org/10.1111/j.1365-2826.2012.02283.x PMid:22283564.
    » http://dx.doi.org/10.1111/j.1365-2826.2012.02283.x
  • Cardoso RC, Alves BRC, Sharpton SM, Williams GL, Amstalden M. Nutritional programming of accelerated puberty in heifers: involvement of pro‐opiomelanocortin neurones in the arcuate nucleus. J Neuroendocrinol. 2015;37(8):647-57. http://dx.doi.org/10.1111/jne.12291 PMid:25944025.
    » http://dx.doi.org/10.1111/jne.12291
  • Clarke SA, Dhillo WS. Phoenixin and its role in reproductive hormone release. Semin Reprod Med. 2019;27(4):191-6. http://dx.doi.org/10.1055/s-0039-3400964 PMid:31972864.
    » http://dx.doi.org/10.1055/s-0039-3400964
  • Constantin S, Wray S. Galanin activates G protein gated inwardly rectifying potassium channels and suppresses Kisspeptin-10 activation of GnRH neurons. Endocrinology. 2016;157(8):3197-212. http://dx.doi.org/10.1210/en.2016-1064 PMid:27359210.
    » http://dx.doi.org/10.1210/en.2016-1064
  • Czujkowska A, Arciszewski MB. Galanin is Co-Expressed with Substance P, Calbindin and Corticotropin-Releasing Factor (CRF) in The Enteric Nervous System of the Wild Boar (Sus scrofa) Small Intestine. Anat Histol Embryol. 2016;45(2):115-23. http://dx.doi.org/10.1111/ahe.12179 PMid:25907507.
    » http://dx.doi.org/10.1111/ahe.12179
  • de Croft S, Boehm U, Herbison AE. Activates arcuate kisspeptin neurons through multiple tachykinin receptors in the male mouse. Endocrinology. 2013;154(8):2750-60. http://dx.doi.org/10.1210/en.2013-1231 PMid:23744641.
    » http://dx.doi.org/10.1210/en.2013-1231
  • de Roux N, Genin E, Carel J-C, Matsuda F, Chaussain J-L, Milgrom E. Hypogonadotropic hypogonadism due to loss of function of the KiSS1-derived peptide receptor GPR54. Proc Natl Acad Sci USA. 2003;100(19):10972-6. http://dx.doi.org/10.1073/pnas.1834399100 PMid:12944565.
    » http://dx.doi.org/10.1073/pnas.1834399100
  • Decourt C, Anger K, Robert V, Lomet D, Bartzen-Sprauer J, Caraty A, Dufourny L, Anderson G, Beltramo M. No Evidence That RFamide-Related Peptide 3 Directly Modulates LH Secretion in the Ewe. Endocrinology. 2016;157(4):1566-75. http://dx.doi.org/10.1210/en.2015-1854 PMid:26862995.
    » http://dx.doi.org/10.1210/en.2015-1854
  • Dhillon SS, Gingerich S, Belsham DD. Neuropeptide Y induces gonadotropin-releasing hormone gene expression directly and through conditioned medium from mHypoE-38 NPY neurons. Regul Pept. 2009;156(1-3):96-103. http://dx.doi.org/10.1016/j.regpep.2009.04.005 PMid:19371763.
    » http://dx.doi.org/10.1016/j.regpep.2009.04.005
  • Ducret E, Anderson GM, Herbison AE. RFamide-related peptide-3, a mammalian gonadotropin-inhibitory hormone ortholog, regulates gonadotropin-releasing hormone neuron firing in the mouse. Endocrinology. 2009;150(6):2799-804. http://dx.doi.org/10.1210/en.2008-1623 PMid:19131572.
    » http://dx.doi.org/10.1210/en.2008-1623
  • Elsaesser F. Stimulation of porcine pituitary luteinizing hormone release by galanin: putative auto/paracrine regulation. Neuroendocrinology. 2001;74(5):288-99. http://dx.doi.org/10.1159/000054696 PMid:11694761.
    » http://dx.doi.org/10.1159/000054696
  • Fang MX, Huang YS, Ye J, Zhang W, Li Y, Nie QH. Identification and characterization of RFRP gene in pigs and its association with reproductive traits. Genet Mol Res. 2014;13(1):1661-71. http://dx.doi.org/10.4238/2014.January.14.8 PMid:24446341.
    » http://dx.doi.org/10.4238/2014.January.14.8
  • Gaigé S, Bonnet MS, Tardivel C, Pinton P, Trouslard J, Jean A, Guzylack L, Troadec JD, Dallaporta M. c-Fos immunoreactivity in the pig brain following deoxynivalenol intoxication: focus on NUCB2/nesfatin-1 expressing neurons. Neurotoxicology. 2013;34:135-49. http://dx.doi.org/10.1016/j.neuro.2012.10.020 PMid:23164930.
    » http://dx.doi.org/10.1016/j.neuro.2012.10.020
  • Garcia IS, Teixeira SA, Costa KA, Marques DBD, Rodrigues GA, Costa TC, Guimarães JD, Otto PI, Saraiva A, Ibelli AMG, Cantão ME, Oliveira HC, Ledur MC, Peixoto JO, Guimarães SEF. L‐Arginine supplementation of gilts during early gestation modulates energy sensitive pathways in pig conceptuses. Mol Reprod Dev. 2020;87(7):819-34. http://dx.doi.org/10.1002/mrd.23397 PMid:32592179.
    » http://dx.doi.org/10.1002/mrd.23397
  • Garcia-Galiano D, Navarro VM, Roa J, Ruiz-Pino F, Sanchez-Garrido MA, Pineda R, Castellano JM, Romero M, Aguilar E, Gaytán F, Diéguez C, Pinilla L, Tena-Sempere M. The anorexigenic neuropeptide, Nesfatin-1, Is indispensable for normal puberty onset in the female rat. J Neurosci. 2010;30(23):7783-92. http://dx.doi.org/10.1523/JNEUROSCI.5828-09.2010 PMid:20534827.
    » http://dx.doi.org/10.1523/JNEUROSCI.5828-09.2010
  • Gibson EM, Humber SA, Jain S, Williams WP 3rd, Zhao S, Bentley GE, Tsutsui K, Kriegsfeld LJ. Alterations in RFamide-related peptide expression are coordinated with the preovulatory luteinizing hormone surge. Endocrinology. 2008;149(10):4958-69. http://dx.doi.org/10.1210/en.2008-0316 PMid:18566114.
    » http://dx.doi.org/10.1210/en.2008-0316
  • Goodman RL, Lehman MN, Smith JT, Coolen LM, de Oliveira CVR, Jafarzadehshirazi MR, Pereira A, Iqbal J, Caraty A, Ciofi P, Clarke IJ. Kisspeptin neurons in the arcuate nucleus of the ewe express both dynorphin A and neurokinin B. Endocrinology. 2007;148(12):5752-60. http://dx.doi.org/10.1210/en.2007-0961 PMid:17823266.
    » http://dx.doi.org/10.1210/en.2007-0961
  • Hashizume T, Saito H, Sawada T, Yaegashi T, Ezzat AA, Sawai K, Yamashita T. Characteristics of stimulation of gonadotropin secretion by kisspeptin-10 in female goats. Anim Reprod Sci. 2010;118(1):37-41. http://dx.doi.org/10.1016/j.anireprosci.2009.05.017 PMid:19574004.
    » http://dx.doi.org/10.1016/j.anireprosci.2009.05.017
  • Herbison AE. Control of puberty onset and fertility by gonadotropin-releasing hormone neurons. Nat Rev Endocrinol. 2016;12(8):452-66. http://dx.doi.org/10.1038/nrendo.2016.70 PMid:27199290.
    » http://dx.doi.org/10.1038/nrendo.2016.70
  • Hinuma S, Shintani Y, Fukusumi S, Iijima N, Matsumoto Y, Hosoya M, Fujii R, Watanabe T, Kikuchi K, Terao Y, Yano T, Yamamoto T, Kawamata Y, Habata Y, Asada M, Kitada C, Kurokawa T, Onda H, Nishimura O, Tanaka M, Ibata Y, Fujino M. New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals. Nat Cell Biol. 2000;2(10):703-8. http://dx.doi.org/10.1038/35036326 PMid:11025660.
    » http://dx.doi.org/10.1038/35036326
  • Ieda N, Uenoyama Y, Tajima Y, Nakata T, Kano M, Naniwa Y, Watanabe Y, Minabe S, Tomikawa J, Inoue N, Matsuda F, Ohkura S, Maeda K, Tsukamura H. KISS1 Gene Expression in the Developing Brain of Female Pigs in Pre- and Peripubertal Periods. J Reprod Dev. 2014;60(4):312-6. http://dx.doi.org/10.1262/jrd.2013-129 PMid:24909600.
    » http://dx.doi.org/10.1262/jrd.2013-129
  • Israel DD, Sheffer-Babila S, de Luca C, Jo Y-H, Liu SM, Xia Q, Spergel DJ, Dun SL, Dun NJ, Chua SC Jr. Effects of Leptin and Melanocortin Signaling Interactions on Pubertal Development and Reproduction. Endocrinology. 2012;153(5):2408-19. http://dx.doi.org/10.1210/en.2011-1822 PMid:22408174.
    » http://dx.doi.org/10.1210/en.2011-1822
  • Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology. LXVIII. Mammalian Bombesin Receptors: Nomenclature, Distribution, Pharmacology, Signaling, and Functions in Normal and Disease States. Pharmacol Rev. 2008;60(1):1-42. http://dx.doi.org/10.1124/pr.107.07108 PMid:18055507.
    » http://dx.doi.org/10.1124/pr.107.07108
  • Jin M, Ma Z, Li X, Su J, Lei Z. The effects of neuromedin S on the hypothalamic-pituitary-testicular axis in male pigs in vitro. Gen Comp Endocrinol. 2019;280:73-81. http://dx.doi.org/10.1016/j.ygcen.2019.04.013 PMid:30981702.
    » http://dx.doi.org/10.1016/j.ygcen.2019.04.013
  • Johnson MA, Tsutsui K, Fraley GS. Rat RFamide-related peptide-3 stimulates GH secretion, inhibits LH secretion, and has variable effects on sex behavior in the adult male rat. Horm Behav. 2007;51(1):171-80. http://dx.doi.org/10.1016/j.yhbeh.2006.09.009 PMid:17113584.
    » http://dx.doi.org/10.1016/j.yhbeh.2006.09.009
  • Kadokawa H, Matsui M, Hayashi K, Matsunaga N, Kawashima C, Shimizu T, Kida K, Miyamoto A. Peripheral administration of kisspeptin-10 increases plasma concentrations of GH as well as LH in prepubertal Holstein heifers. J Endocrinol. 2008;196(2):331-4. http://dx.doi.org/10.1677/JOE-07-0504 PMid:18252956.
    » http://dx.doi.org/10.1677/JOE-07-0504
  • Kadokawa H, Shibata M, Tanaka Y, Kojima T, Matsumoto K, Oshima K, Yamamoto N. Bovine C-terminal octapeptide of RFamide-related peptide-3 suppresses luteinizing hormone (LH) secretion from the pituitary as well as pulsatile LH secretion in bovines. Domest Anim Endocrinol. 2009;36(4):219-24. http://dx.doi.org/10.1016/j.domaniend.2009.02.001 PMid:19328642.
    » http://dx.doi.org/10.1016/j.domaniend.2009.02.001
  • Kalló I, Vida B, Deli L, Molnár CS, Hrabovszky E, Caraty A, Ciofi P, Coen CW, Liposits Z. Co-localisation of kisspeptin with galanin or neurokinin B in afferents to mouse GnRH neurones. J Neuroendocrinol. 2012;24(3):464-76. http://dx.doi.org/10.1111/j.1365-2826.2011.02262.x PMid:22129075.
    » http://dx.doi.org/10.1111/j.1365-2826.2011.02262.x
  • Klenke U, Constantin S, Wray S. Directly Inhibits neuronal activity in a subpopulation of gonadotropin-releasing hormone-1 neurons via Y1 receptors. Endocrinology. 2010;151(6):2736-46. http://dx.doi.org/10.1210/en.2009-1198 PMid:20351316.
    » http://dx.doi.org/10.1210/en.2009-1198
  • Kriegsfeld LJ, Mei DF, Bentley GE, Ubuka T, Mason AO, Inoue K, Ukena K, Tsutsui K, Silver R. Identification and characterization of a gonadotropin-inhibitory system in the brains of mammals. Proc Natl Acad Sci USA. 2006;103(7):2410-5. http://dx.doi.org/10.1073/pnas.0511003103 PMid:16467147.
    » http://dx.doi.org/10.1073/pnas.0511003103
  • Kriegsfeld LJ. Driving reproduction: RFamide peptides behind the wheel. Horm Behav. 2006;50(5):655-66. http://dx.doi.org/10.1016/j.yhbeh.2006.06.004 PMid:16876801.
    » http://dx.doi.org/10.1016/j.yhbeh.2006.06.004
  • Lane RL, Whitaker BD. Melatonin and tannic acid supplementation in vitro improve fertilization and embryonic development in pigs. Anim Reprod. 2018;15(2):118-23. http://dx.doi.org/10.21451/1984-3143-AR2016-937 PMid:34122642.
    » http://dx.doi.org/10.21451/1984-3143-AR2016-937
  • Legagneux K, Bernard-Franchi G, Poncet F, La Roche A, Colard C, Fellmann D, Pralong F, Risold PY. Distribution and genesis of the RFRP-producing neurons in the rat brain: comparison with melanin-concentrating hormone- and hypocretin-containing neurons. Neuropeptides. 2009;43(1):13-9. http://dx.doi.org/10.1016/j.npep.2008.11.001 PMid:19101033.
    » http://dx.doi.org/10.1016/j.npep.2008.11.001
  • Lents CA, Heidorn NL, Barb CR, Ford JJ. Central and peripheral administration of kisspeptin activates gonadotropin but not somatotropin secretion in prepubertal gilts. Reproduction. 2008;135(6):879-87. http://dx.doi.org/10.1530/REP-07-0502 PMid:18339687.
    » http://dx.doi.org/10.1530/REP-07-0502
  • Lents CA, Lindo AN, Hileman SM, Nonneman DJ. Physiological and genomic insight into neuroendocrine regulation of puberty in gilts. Domest Anim Endocrinol. 2020;73:106446. http://dx.doi.org/10.1016/j.domaniend.2020.106446 PMid:32199704.
    » http://dx.doi.org/10.1016/j.domaniend.2020.106446
  • Lents CA. Review: kisspeptin and reproduction in the pig. Animal. 2019;13(12):2986-99. http://dx.doi.org/10.1017/S1751731119001666 PMid:31317853.
    » http://dx.doi.org/10.1017/S1751731119001666
  • Lepiarczyk E, Bossowska A, Majewska M, Skowrońska A, Kaleczyc J, Majewski M. Distribution and chemical coding of phoenixin-immunoreactive nerve structures in the spinal cord of the pig. Ann Anat. 2020;232:151559. http://dx.doi.org/10.1016/j.aanat.2020.151559 PMid:32569824.
    » http://dx.doi.org/10.1016/j.aanat.2020.151559
  • Li X, Su J, Fang R, Zheng L, Lei R, Wang X, Lei Z, Jin M, Jiao Y, Hou Y, Guo T, Ma Z. The effects of RFRP-3, the mammalian ortholog of GnIH, on the female pig reproductive axis in vitro. Mol Cell Endocrinol. 2013;372(1-2):65-72. http://dx.doi.org/10.1016/j.mce.2013.03.015 PMid:23541949.
    » http://dx.doi.org/10.1016/j.mce.2013.03.015
  • Lindo A. Characterization of KNDy neuronal activity in gilts: distribution and effect of a progestin [thesis]. Morgantown: West Virginia University; 2018.
  • Ma Z, Su J, Guo T, Jin M, Li X, Lei Z, Hou Y, Li X, Jia C, Zhang Z, Ahmed E. Neuromedin B and its receptor: gene cloning, tissue distribution and expression levels of the reproductive axis in pigs. PLoS ONE. 2016 Mar 24;11(3):e0151871. https://doi.org/10.1371/journal.pone.0151871
    » https://doi.org/10.1371/journal.pone.0151871
  • Ma Z, Zhao Y, Yao Y, Lei Z, Jin M, Li X, Jia C, Zhang Z, Li X, Su J. Postnatal developmental of Neuromedin S and its receptor in the male Xiaomeishan pig reproductive axis. Anim Reprod Sci. 2017;181:115-24. http://dx.doi.org/10.1016/j.anireprosci.2017.03.023 PMid:28389048.
    » http://dx.doi.org/10.1016/j.anireprosci.2017.03.023
  • Ma Z, Zhang Y, Su J, Yang S, Qiao W, Li X, Lei Z, Cheng L, An N, Wang W, Feng Y, Zhang J. Effects of neuromedin B on steroidogenesis, cell proliferation and apoptosis in porcine Leydig cells. J Mol Endocrinol. 2018;61(1):13-23. http://dx.doi.org/10.1530/JME-17-0242 PMid:29632025.
    » http://dx.doi.org/10.1530/JME-17-0242
  • Magee C, Foradori CD, Bruemmer JE, Arreguin-Arevalo JA, McCue PM, Handa RJ, Squires EL, Clay CM. Biological and anatomical evidence for kisspeptin regulation of the hypothalamic-pituitary-gonadal axis of estrous horse mares. Endocrinology. 2009;150(6):2813-21. http://dx.doi.org/10.1210/en.2008-1698 PMid:19228887.
    » http://dx.doi.org/10.1210/en.2008-1698
  • Marín-García PJ, Llobat L. How does protein nutrition affect the epigenetic changes in pig? A review. Animals (Basel). 2021;11(2):544. http://dx.doi.org/10.3390/ani11020544 PMid:33669864.
    » http://dx.doi.org/10.3390/ani11020544
  • Messager S, Chatzidaki EE, Ma D, Hendrick AG, Zahn D, Dixon J, Thresher RR, Malinge I, Lomet D, Carlton MB, Colledge WH, Caraty A, Aparicio SA. Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54. Proc Natl Acad Sci USA. 2005;102(5):1761-6. http://dx.doi.org/10.1073/pnas.0409330102 PMid:15665093.
    » http://dx.doi.org/10.1073/pnas.0409330102
  • Millar RP. GnRHs and GnRH receptors. Anim Reprod Sci. 2005;88(1–2):5-28. http://dx.doi.org/10.1016/j.anireprosci.2005.05.032 PMid:16140177.
    » http://dx.doi.org/10.1016/j.anireprosci.2005.05.032
  • Mori K, Miyazato M, Ida T, Murakami N, Serino R, Ueta Y, Kojima M, Kangawa K. Identification of neuromedin S and its possible role in the mammalian circadian oscillator system. EMBO J. 2005;24(2):325-35. http://dx.doi.org/10.1038/sj.emboj.7600526 PMid:15635449.
    » http://dx.doi.org/10.1038/sj.emboj.7600526
  • Murakami M, Matsuzaki T, Iwasa T, Yasui T, Irahara M, Osugi T, Tsutsui K. Hypophysiotropic role of RFamide-related peptide-3 in the inhibition of LH secretion in female rats. J Endocrinol. 2008;199(1):105-12. http://dx.doi.org/10.1677/JOE-08-0197 PMid:18653621.
    » http://dx.doi.org/10.1677/JOE-08-0197
  • Muro BBD, Leal DF, Carnevale RF, Torres MA, Mendonça MV, Nakasone DH, Martinez CHG, Ravagnani GM, Monteiro MS, Poor AP, Martins SMMK, Viau P, Oliveira CA, Castro RVG, Bessi BW, Bressan FF, Pulz LH, Strefezzi RF, Almond GW, Andrade AFC. Altrenogest during early pregnancy modulates uterine glandular epithelium and endometrial growth factor expression at the time implantation in pigs. Anim Reprod. 2021;18(1):e20200431. http://dx.doi.org/10.1590/1984-3143-ar2020-0431 PMid:34122654.
    » http://dx.doi.org/10.1590/1984-3143-ar2020-0431
  • Navarro VM, Castellano JM, McConkey SM, Pineda R, Ruiz-Pino F, Pinilla L, Clifton DK, Tena-Sempere M, Steiner RA. Interactions between kisspeptin and neurokinin B in the control of GnRH secretion in the female rat. Am J Physiol Endocrinol Metab. 2011;300(1):E202-10. http://dx.doi.org/10.1152/ajpendo.00517.2010 PMid:21045176.
    » http://dx.doi.org/10.1152/ajpendo.00517.2010
  • Navarro VM, Gottsch ML, Chavkin C, Okamura H, Clifton DK, Steiner RA. Regulation of Gonadotropin-Releasing Hormone Secretion by Kisspeptin/Dynorphin/Neurokinin B Neurons in the Arcuate Nucleus of the Mouse. J Neurosci. 2009;29(38):11859-66. http://dx.doi.org/10.1523/JNEUROSCI.1569-09.2009 PMid:19776272.
    » http://dx.doi.org/10.1523/JNEUROSCI.1569-09.2009
  • Nguyen XP, Nakamura T, Osuka S, Bayasula B, Nakanishi N, Kasahara Y, Muraoka A, Hayashi S, Nagai T, Murase T, Goto M, Iwase A, Kikkawa F. Effect of the neuropeptide phoenixin and its receptor GPR173 during folliculogenesis. Reproduction. 2019;158(1):25-34. http://dx.doi.org/10.1530/REP-19-0025 PMid:30933929.
    » http://dx.doi.org/10.1530/REP-19-0025
  • Ohki-Hamazaki H, Iwabuchi M, Maekawa F. Development and function of bombesin-like peptides and their receptors. Int J Dev Biol. 2005;49(2-3):293-300. http://dx.doi.org/10.1387/ijdb.041954ho PMid:15906244.
    » http://dx.doi.org/10.1387/ijdb.041954ho
  • Ohtaki T, Shintani Y, Honda S, Matsumoto H, Hori A, Kanehashi K, Terao Y, Kumano S, Takatsu Y, Masuda Y, Ishibashi Y, Watanabe T, Asada M, Yamada T, Suenaga M, Kitada C, Usuki S, Kurokawa T, Onda H, Nishimura O, Fujino M. Metastasis suppressor gene KiSS-1 encodes peptide ligand of a G-protein-coupled receptor. Nature. 2001;411(6837):613-7. http://dx.doi.org/10.1038/35079135 PMid:11385580.
    » http://dx.doi.org/10.1038/35079135
  • Óvilo C, Fernández A, Fernández AI, Folch JM, Varona L, Benítez R, Nuñez Y, Rodríguez C, Silió L. Hypothalamic expression of porcine leptin receptor (LEPR), neuropeptide Y (NPY), and cocaine- and amphetamine-regulated transcript (CART) genes is influenced by LEPR genotype. Mamm Genome. 2010;21(11–12):583-91. http://dx.doi.org/10.1007/s00335-010-9307-1 PMid:21128076.
    » http://dx.doi.org/10.1007/s00335-010-9307-1
  • Peltoniemi O, Björkman S, Oropeza-Moe M, Oliviero C. Developments of reproductive management and biotechnology in the pig. Anim Reprod. 2019;16(3):524-38. http://dx.doi.org/10.21451/1984-3143-AR2019-0055 PMid:32435295.
    » http://dx.doi.org/10.21451/1984-3143-AR2019-0055
  • Pineda R, Garcia-Galiano D, Sanchez-Garrido MA, Romero M, Ruiz-Pino F, Aguilar E, Dijcks FA, Blomenröhr M, Pinilla L, van Noort PI, Tena-Sempere M. Characterization of the inhibitory roles of RFRP3, the mammalian ortholog of GnIH, in the control of gonadotropin secretion in the rat: in vivo and in vitro studies. Am J Physiol Endocrinol Metab. 2010;299(1):E39-46. http://dx.doi.org/10.1152/ajpendo.00108.2010 PMid:20424142.
    » http://dx.doi.org/10.1152/ajpendo.00108.2010
  • Qi Y, Oldfield BJ, Clarke IJ. Projections of RFamide-related peptide-3 neurones in the ovine hypothalamus, with special reference to regions regulating energy balance and reproduction. J Neuroendocrinol. 2009;21(8):690-7. http://dx.doi.org/10.1111/j.1365-2826.2009.01886.x PMid:19500220.
    » http://dx.doi.org/10.1111/j.1365-2826.2009.01886.x
  • Ralph C, Kirkwood R, Tilbrook A. A single intravenous injection of Kisspeptin evokes an increase in luteinising hormone in 15- and 18- week-old gilts. Anim Reprod Sci. 2017;57(12):2469. http://dx.doi.org/10.1071/ANv57n12Ab067
    » http://dx.doi.org/10.1071/ANv57n12Ab067
  • Ramaswamy S, Seminara SB, Plant TM. Evidence from the agonadal juvenile male rhesus monkey (Macaca mulatta) for the view that the action of neurokinin B to Trigger Gonadotropin-Releasing Hormone Release Is Upstream from the Kisspeptin Receptor. Neuroendocrinology. 2011;94(3):237-45. http://dx.doi.org/10.1159/000329045 PMid:21832818.
    » http://dx.doi.org/10.1159/000329045
  • Redmond JS, Baez-Sandoval GM, Spell KM, Spencer TE, Lents CA, Williams GL, Amstalden M. Developmental Changes in Hypothalamic Kiss1 Expression during Activation of the Pulsatile Release of Luteinising Hormone in Maturing Ewe Lambs. J Neuroendocrinol. 2011;23(9):815-22. http://dx.doi.org/10.1111/j.1365-2826.2011.02177.x PMid:21679258.
    » http://dx.doi.org/10.1111/j.1365-2826.2011.02177.x
  • Rizwan MZ, Porteous R, Herbison AE, Anderson GM. Cells expressing RFamide-related peptide-1/3, the mammalian gonadotropin-inhibitory hormone orthologs, are not hypophysiotropic neuroendocrine neurons in the rat. Endocrinology. 2009;150(3):1413-20. http://dx.doi.org/10.1210/en.2008-1287 PMid:19008316.
    » http://dx.doi.org/10.1210/en.2008-1287
  • Roa J, Herbison AE. Direct regulation of gnrh neuron excitability by arcuate nucleus POMC and NPY neuron neuropeptides in female mice. Endocrinology. 2012;153(11):5587-99. http://dx.doi.org/10.1210/en.2012-1470 PMid:22948210.
    » http://dx.doi.org/10.1210/en.2012-1470
  • Roesler R, Kent P, Schröder N, Schwartsmann G, Merali Z. Bombesin receptor regulation of emotional memory. Rev Neurosci. 2012;23(5–6):571-86. PMid:23096238.
  • Seminara SB, Messager S, Chatzidaki EE, Thresher RR, Acierno JS Jr, Shagoury JK, Bo-Abbas Y, Kuohung W, Schwinof KM, Hendrick AG, Zahn D, Dixon J, Kaiser UB, Slaugenhaupt SA, Gusella JF, O’Rahilly S, Carlton MBL, Crowley WF Jr, Aparicio SAJR, Colledge WH. The GPR54 gene as a regulator of puberty. N Engl J Med. 2003;349(17):1614-27. http://dx.doi.org/10.1056/NEJMoa035322 PMid:14573733.
    » http://dx.doi.org/10.1056/NEJMoa035322
  • Semple RK, Achermann JC, Ellery J, Farooqi IS, Karet FE, Stanhope RG, O’rahilly S, Aparicio SA. Two novel missense mutations in G protein-coupled receptor 54 in a patient with hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 2005;90(3):1849-55. http://dx.doi.org/10.1210/jc.2004-1418 PMid:15598687.
    » http://dx.doi.org/10.1210/jc.2004-1418
  • Shahab M, Mastronardi C, Seminara SB, Crowley WF, Ojeda SR, Plant TM. Increased hypothalamic GPR54 signaling: A potential mechanism for initiation of puberty in primates. Proc Natl Acad Sci USA. 2005;102(6):2129-34. http://dx.doi.org/10.1073/pnas.0409822102 PMid:15684075.
    » http://dx.doi.org/10.1073/pnas.0409822102
  • Siawrys G, Buchowski H. Modulation of anterior pituitary cell luteinizing hormone secretory activity by neuropeptide Y in early pregnant pigs. J Physiol Pharmacol. 2018;69(5):719-26. https://doi.org/10.26402/jpp.2018.5.06
    » https://doi.org/10.26402/jpp.2018.5.06
  • Silva PCP, Brasil OO, Souto PLG, Moreira NH, Silva JP, Silva BDM, Ramos AF. Fixed-time artificial insemination protocols on brazilian locally adapted breed gilts on ovulatory response and embryo production. Anim Reprod. 2021;18(1):e20200776. http://dx.doi.org/10.1590/1984-3143-ar2020-0776 PMid:34122655.
    » http://dx.doi.org/10.1590/1984-3143-ar2020-0776
  • Smith JT, Coolen LM, Kriegsfeld LJ, Sari IP, Jaafarzadehshirazi MR, Maltby M, Bateman K, Goodman RL, Tilbrook AJ, Ubuka T, Bentley GE, Clarke IJ, Lehman MN. Variation in Kisspeptin and RFamide-related peptide (RFRP) expression and terminal connections to gonadotropin-releasing hormone neurons in the brain: a novel medium for seasonal breeding in the sheep. Endocrinology. 2008a;149(11):5770-82. http://dx.doi.org/10.1210/en.2008-0581 PMid:18617612.
    » http://dx.doi.org/10.1210/en.2008-0581
  • Smith JT, Rao A, Pereira A, Caraty A, Millar RP, Clarke IJ. Kisspeptin is present in ovine hypophysial portal blood but does not increase during the preovulatory luteinizing hormone surge: evidence that gonadotropes are not direct targets of kisspeptin in vivo. Endocrinology. 2008b;149(4):1951-9. http://dx.doi.org/10.1210/en.2007-1425 PMid:18162520.
    » http://dx.doi.org/10.1210/en.2007-1425
  • Smith JT, Li Q, Yap KS, Shahab M, Roseweir AK, Millar RP, Clarke IJ. Kisspeptin is essential for the full preovulatory LH surge and stimulates GnRH release from the isolated ovine median eminence. Endocrinology. 2011;152(3):1001-12. http://dx.doi.org/10.1210/en.2010-1225 PMid:21239443.
    » http://dx.doi.org/10.1210/en.2010-1225
  • Smith JT, Young IR, Veldhuis JD, Clarke IJ. Gonadotropin-inhibitory hormone (GnIH) secretion into the ovine hypophyseal portal system. Endocrinology. 2012;153(7):3368-75. http://dx.doi.org/10.1210/en.2012-1088 PMid:22549225.
    » http://dx.doi.org/10.1210/en.2012-1088
  • Sonstegard T, Fahrenkrug S, Carlson D. Precision animal breeding to make genetically castrated animals for improved animal welfare and alternative breeding applications. J Anim Sci. 2017;95(suppl 2):149-50. http://dx.doi.org/10.2527/asasmw.2017.307
    » http://dx.doi.org/10.2527/asasmw.2017.307
  • Spergel DJ. Neuropeptidergic modulation of GnRH neuronal activity and GnRH secretion controlling reproduction: insights from recent mouse studies. Cell Tissue Res. 2019;375(1):179-91. http://dx.doi.org/10.1007/s00441-018-2893-z PMid:30078104.
    » http://dx.doi.org/10.1007/s00441-018-2893-z
  • Thompson EL, Patterson M, Murphy KG, Smith KL, Dhillo WS, Todd JF, Ghatei MA, Bloom SR. Central and peripheral administration of kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis. J Neuroendocrinol. 2004;16(10):850-8. http://dx.doi.org/10.1111/j.1365-2826.2004.01240.x PMid:15500545.
    » http://dx.doi.org/10.1111/j.1365-2826.2004.01240.x
  • Thorson JF, Desaulniers AT, Lee C, White BR, Ford JJ, Lents CA. The role of RFamide-related peptide 3 (RFRP3) in regulation of the neuroendocrine reproductive and growth axes of the boar. Anim Reprod Sci. 2015;159:60-5. http://dx.doi.org/10.1016/j.anireprosci.2015.05.013 PMid:26051609.
    » http://dx.doi.org/10.1016/j.anireprosci.2015.05.013
  • Thorson JF, Heidorn NL, Ryu V, Czaja K, Nonneman DJ, Barb CR, Hausman GJ, Rohrer GA, Prezotto LD, McCosh RB, Wright EC, White BR, Freking BA, Oliver WT, Hileman SM, Lents CA. Relationship of neuropeptide FF receptors with pubertal maturation of gilts. Biol Reprod. 2017;96(3):617-34. http://dx.doi.org/10.1095/biolreprod.116.144998 PMid:28339619.
    » http://dx.doi.org/10.1095/biolreprod.116.144998
  • Thorson JF, Prezotto LD, Adams H, Petersen SL, Clapper JA, Wright EC, Oliver WT, Freking BA, Foote AP, Berry ED, Nonneman DJ, Lents CA. Energy balance affects pulsatile secretion of luteinizing hormone from the adenohypophesis and expression of neurokinin B in the hypothalamus of ovariectomized gilts†. Biol Reprod. 2018;99(2):433-45. http://dx.doi.org/10.1093/biolre/ioy069 PMid:30101293.
    » http://dx.doi.org/10.1093/biolre/ioy069
  • Thorson JF, Prezotto LD, Cardoso RC, Sharpton SM, Edwards JF, Welsh TH Jr, Riggs AC, Amstalden M, Gary GL. Hypothalamic distribution, adenohypophyseal receptor expression, and ligand functionality of rfamide-related peptide 3 in the mare during the breeding and nonbreeding seasons. Biol Reprod [serial on the Internet]. 2014 Feb 1 [cited 2021 Feb 27];90(2):1-9. Available from: https://academic.oup.com/biolreprod/article-lookup/doi/10.1095/biolreprod.113.112185
    » https://academic.oup.com/biolreprod/article-lookup/doi/10.1095/biolreprod.113.112185
  • Tomikawa J, Homma T, Tajima S, Shibata T, Inamoto Y, Takase K, Inoue N, Ohkura S, Uenoyama Y, Maeda K, Tsukamura H. Molecular characterization and estrogen regulation of hypothalamic KISS1 gene in the pig. Biol Reprod. 2010;82(2):313-9. http://dx.doi.org/10.1095/biolreprod.109.079863 PMid:19828777.
    » http://dx.doi.org/10.1095/biolreprod.109.079863
  • Topaloglu AK, Reimann F, Guclu M, Yalin AS, Kotan LD, Porter KM, Serin A, Mungan NO, Cook JR, Ozbek MN, Imamoglu S, Akalin NS, Yuksel B, O’Rahilly S, Semple RK. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet. 2009;41(3):354-8. http://dx.doi.org/10.1038/ng.306 PMid:19079066.
    » http://dx.doi.org/10.1038/ng.306
  • Treen AK, Luo V, Belsham DD. Phoenixin activates immortalized GnRH and kisspeptin neurons through the novel receptor GPR173. Mol Endocrinol. 2016;30(8):872-88. http://dx.doi.org/10.1210/me.2016-1039 PMid:27268078.
    » http://dx.doi.org/10.1210/me.2016-1039
  • Tsutsumi R, Webster NJG. GnRH pulsatility, the pituitary response and reproductive dysfunction. Endocr J. 2009;56(6):729-37. http://dx.doi.org/10.1507/endocrj.K09E-185 PMid:19609045.
    » http://dx.doi.org/10.1507/endocrj.K09E-185
  • Weems PW, Lehman MN, Coolen LM, Goodman RL. The roles of neurokinins and endogenous opioid peptides in control of pulsatile LH secretion. In: Litwack G, editor. Vitamins and hormones [Internet]. USA: Elsevier; 2018 [cited 2021 Feb 27]. p. 89-135. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0083672918300116
    » https://linkinghub.elsevier.com/retrieve/pii/S0083672918300116
  • Wójcik-Gładysz A, Polkowska J. Neuropeptide Y--a neuromodulatory link between nutrition and reproduction at the central nervous system level. Reprod Biol. 2006;6(Suppl. 2):21-8. PMid:17220938.
  • Wu M, Dumalska I, Morozova E, Van Den Pol AN, Alreja M. Gonadotropin inhibitory hormone inhibits basal forebrain vGluT2-gonadotropin-releasing hormone neurons via a direct postsynaptic mechanism. J Physiol. 2009;587(Pt 7):1401-11. http://dx.doi.org/10.1113/jphysiol.2008.166447 PMid:19204051.
    » http://dx.doi.org/10.1113/jphysiol.2008.166447
  • Wylot B, Tworus K, Okrasa S. the effects of mu-, delta- and kappa-opioid receptor activation on luteinizing and follicle-stimulating hormone secretion from porcine pituitary cells. J Physiol Pharmacol. 2013;64(4):505-11. PMid:24101398.
  • Xu G, Li J, Zhang D, Su T, Li X, Cui S. HSP70 inhibits pig pituitary gonadotrophin synthesis and secretion by regulating the corticotropin-releasing hormone signaling pathway and targeting SMAD3. Domest Anim Endocrinol. 2021;74:106533. http://dx.doi.org/10.1016/j.domaniend.2020.106533 PMid:32992141.
    » http://dx.doi.org/10.1016/j.domaniend.2020.106533
  • Yang G, Su J, Yao Y, Lei Z, Zhang G, Li X. The regulatory mechanism of neuromedin S on luteinizing hormone in pigs. Anim Reprod Sci. 2010;122(3–4):367-74. http://dx.doi.org/10.1016/j.anireprosci.2010.10.011 PMid:21071159.
    » http://dx.doi.org/10.1016/j.anireprosci.2010.10.011
  • Yang G, Su J, Yao Y, Lei Z, Zhang G, Liu Y, Liu J, Li X. Distribution of neuromedin S and its receptor NMU2R in pigs. Res Vet Sci. 2012;92(2):180-6. http://dx.doi.org/10.1016/j.rvsc.2010.11.013 PMid:21185043.
    » http://dx.doi.org/10.1016/j.rvsc.2010.11.013
  • Yano T, Iijima N, Kakihara K, Hinuma S, Tanaka M, Ibata Y. Localization and neuronal response of RFamide related peptides in the rat central nervous system. Brain Res. 2003;982(2):156-67. http://dx.doi.org/10.1016/S0006-8993(03)02877-4 PMid:12915251.
    » http://dx.doi.org/10.1016/S0006-8993(03)02877-4
  • Yoshida H, Habata Y, Hosoya M, Kawamata Y, Kitada C, Hinuma S. Molecular properties of endogenous RFamide-related peptide-3 and its interaction with receptors. Biochim Biophys Acta. 2003;1593(2-3):151-7. PMid:12581859.
  • Yosten GLC, Lyu R-M, Hsueh AJW, Avsian-Kretchmer O, Chang J-K, Tullock CW, Dun SL, Dun N, Samson WK. A novel reproductive peptide, phoenixin. J Neuroendocrinol. 2013;25(2):206-15. http://dx.doi.org/10.1111/j.1365-2826.2012.02381.x PMid:22963497.
    » http://dx.doi.org/10.1111/j.1365-2826.2012.02381.x
  • Zhou D, Zhuo Y, Che L, Lin Y, Fang Z, Wu D. Nutrient restriction induces failure of reproductive function and molecular changes in hypothalamus–pituitary–gonadal axis in postpubertal gilts. Mol Biol Rep. 2014;41(7):4733-42. http://dx.doi.org/10.1007/s11033-014-3344-x PMid:24728609.
    » http://dx.doi.org/10.1007/s11033-014-3344-x
  • Zmijewska A, Czelejewska W, Dziekonski M, Gajewska A, Franczak A, Okrasa S. Effect of kisspeptin and RFamide-related peptide-3 on the synthesis and secretion of LH by pituitary cells of pigs during the estrous cycle. Anim Reprod Sci. 2020;214:106275. http://dx.doi.org/10.1016/j.anireprosci.2020.106275 PMid:32087907.
    » http://dx.doi.org/10.1016/j.anireprosci.2020.106275

Publication Dates

  • Publication in this collection
    10 Dec 2021
  • Date of issue
    2021

History

  • Received
    19 July 2021
  • Accepted
    10 Nov 2021
Colégio Brasileiro de Reprodução Animal Coronel José dias Bicalho, 1224, CEP: , 31275-050, Belo Horizonte, MG - Brasil, Tel.: 55-31-3491 7122 - Belo Horizonte - MG - Brazil
E-mail: animreprod.journal@gmail.com