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Frontiers in Endocrinology 2023The suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level...
The transcription factor VAX1 in VIP neurons of the suprachiasmatic nucleus impacts circadian rhythm generation, depressive-like behavior, and the reproductive axis in a sex-specific manner in mice.
BACKGROUND
The suprachiasmatic nucleus (SCN) within the hypothalamus is a key brain structure required to relay light information to the body and synchronize cell and tissue level rhythms and hormone release. Specific subpopulations of SCN neurons, defined by their peptide expression, regulate defined SCN output. Here we focus on the vasoactive intestinal peptide (VIP) expressing neurons of the SCN. SCN VIP neurons are known to regulate circadian rhythms and reproductive function.
METHODS
To specifically study SCN VIP neurons, we generated a novel knock out mouse line by conditionally deleting the SCN enriched transcription factor, Ventral Anterior Homeobox 1 (Vax1), in VIP neurons (Vax1; Vax1:Vip).
RESULTS
We found that Vax1 females presented with lengthened estrous cycles, reduced circulating estrogen, and increased depressive-like behavior. Further, Vax1 males and females presented with a shortened circadian period in locomotor activity and SCN circadian period. On a molecular level, the shortening of the SCN period was driven, at least partially, by a direct regulatory role of VAX1 on the circadian clock genes and . Interestingly, Vax1 females presented with increased expression of arginine vasopressin () in the paraventricular nucleus, which resulted in increased circulating corticosterone. SCN VIP and AVP neurons regulate the reproductive gonadotropin-releasing hormone (GnRH) and kisspeptin neurons. To determine how the reproductive neuroendocrine network was impacted in Vax1 mice, we assessed GnRH sensitivity to a kisspeptin challenge . We found that GnRH neurons in Vax1 females, but not males, had an increased sensitivity to kisspeptin, leading to increased luteinizing hormone release. Interestingly, Vax1 males showed a small, but significant increase in total sperm and a modest delay in pubertal onset. Both male and female Vax1 mice were fertile and generated litters comparable in size and frequency to controls.
CONCLUSION
Together, these data identify VAX1 in SCN VIP neurons as a neurological overlap between circadian timekeeping, female reproduction, and depressive-like symptoms in mice, and provide novel insight into the role of SCN VIP neurons.
Topics: Male; Female; Animals; Mice; Transcription Factors; Vasoactive Intestinal Peptide; Kisspeptins; Semen; Suprachiasmatic Nucleus; Reproduction; Neurons; Circadian Rhythm; Gonadotropin-Releasing Hormone; Neuropeptides; Homeodomain Proteins
PubMed: 38205198
DOI: 10.3389/fendo.2023.1269672 -
Autoimmunity Dec 2024Recurrent spontaneous abortions (RSA) affect reproductive health and increase the risk of subsequent abortions. To investigate the role of KISS-1/GPR-54 signaling in RSA...
Recurrent spontaneous abortions (RSA) affect reproductive health and increase the risk of subsequent abortions. To investigate the role of KISS-1/GPR-54 signaling in RSA progression. Villus tissue was collected from RSA patients, and human trophoblastic HTR-8/SVneo cells were used. KISS-1 and GRP54 levels were detected using RT-qPCR and immunohistochemistry. Western blotting was performed to analyze ZO-1 and ZEB1 levels. Cell proliferation was determined CCK-8 and cell clone formation assays. Transwell assays were performed to assess cell migration and invasion abilities. KISS-1 was down-regulated in the villus tissues of RSA patients. KISS-1 overexpression dramatically inhibited trophoblast proliferation, migration, and invasion. Mechanistically, ZEB1 expression was down-regulated, whereas ZO-1 expression was up-regulated, after KISS-1 overexpression. GPR54 silencing neutralized the effect of KISS-1 in HTR-8/SVneo cells. Additionally, KISS-1 overexpression inactivated the PI3K/AKT signaling pathway through GRP54. The KISS-1/GPR-54 signaling axis regulates RSA progression by regulating the PI3K/AKT signaling pathway.
Topics: Female; Humans; Pregnancy; Cell Movement; Cell Proliferation; Kisspeptins; Phosphatidylinositol 3-Kinases; Pre-Eclampsia; Proto-Oncogene Proteins c-akt; Signal Transduction
PubMed: 38155490
DOI: 10.1080/08916934.2023.2297564 -
Endocrine Regulations Jan 2023Hypothalamic-pituitary gonadal (HPG) axis is responsible for the development and regulation of the female reproductive system. In polycystic ovary syndrome (PCOS), there... (Review)
Review
Hypothalamic-pituitary gonadal (HPG) axis is responsible for the development and regulation of the female reproductive system. In polycystic ovary syndrome (PCOS), there is a disturbance in the HPG axis. Kisspeptin, a neuropeptide produced by the KISS1 gene, plays a vital role in the regulation of HPG axis by binding with its receptors KISS1R/GPR54, and stimulates gonadotropin secretion from the hypothalamus into pituitary to release luteinizing hormone (LH) and follicle stimulating hormone (FSH). Polymorphisms or mutations in the KISS1 gene can cause disturbance in the kisspeptin signaling pathway and is thought to disrupt HPG axis. Altered signaling of kisspeptin can cause abnormal secretion of GnRH pulse, which leads to increased LH/FSH ratio, thereby affecting androgen levels and ovulation. The increased levels of androgen worsen the symptoms of PCOS. In the present article, we review the molecular physiology and pathology of kisspeptin and how it is responsible for the development of PCOS. The goal of this review article is to provide an overview and metabolic profile of kisspeptin in PCOS patients and the expression of kisspeptin in PCOS animal models. In the present article, we also review the molecular physiology and pathology of kisspeptin and how it is responsible for the development of PCOS.
Topics: Animals; Female; Humans; Polycystic Ovary Syndrome; Kisspeptins; Androgens; Luteinizing Hormone; Follicle Stimulating Hormone
PubMed: 38127687
DOI: 10.2478/enr-2023-0032 -
ELife Dec 2023Evidence suggests that estradiol-sensing preoptic area GABA neurons are involved in the preovulatory surge mechanism necessary for ovulation. In vivo CRISPR-Cas9 editing...
Evidence suggests that estradiol-sensing preoptic area GABA neurons are involved in the preovulatory surge mechanism necessary for ovulation. In vivo CRISPR-Cas9 editing was used to achieve a 60-70% knockdown in estrogen receptor alpha (ESR1) expression by GABA neurons located within the regions of the rostral periventricular area of the third ventricle (RP3V) and medial preoptic nuclei (MPN) in adult female mice. Mice exhibited variable reproductive phenotypes with the only significant finding being mice with bilateral ESR1 deletion in RP3V GABA neurons having reduced cFos expression in gonadotropin-releasing hormone (GnRH) neurons at the time of the surge. One sub-population of RP3V GABA neurons expresses kisspeptin. Re-grouping ESR1-edited mice on the basis of their RP3V kisspeptin expression revealed a highly consistent phenotype; mice with a near-complete loss of kisspeptin immunoreactivity displayed constant estrus and failed to exhibit surge activation but retained pulsatile luteinizing hormone (LH) secretion. These observations demonstrate that ESR1-expressing GABA-kisspeptin neurons in the RP3V are essential for the murine preovulatory LH surge mechanism.
Topics: Mice; Female; Animals; Kisspeptins; CRISPR-Cas Systems; Gonadotropin-Releasing Hormone; GABAergic Neurons; Estrous Cycle; gamma-Aminobutyric Acid
PubMed: 38126277
DOI: 10.7554/eLife.90959 -
Journal of Molecular Endocrinology Feb 2024The exact neural construct underlying the dynamic secretion of gonadotrophin-releasing hormone (GnRH) has only recently been identified despite the detection of... (Review)
Review
The exact neural construct underlying the dynamic secretion of gonadotrophin-releasing hormone (GnRH) has only recently been identified despite the detection of multiunit electrical activity volleys associated with pulsatile luteinising hormone (LH) secretion four decades ago. Since the discovery of kisspeptin/neurokinin B/dynorphin neurons in the mammalian hypothalamus, there has been much research into the role of this neuronal network in controlling the oscillatory secretion of gonadotrophin hormones. In this review, we provide an update of the progressive application of cutting-edge techniques combined with mathematical modelling by the neuroendocrine community, which are transforming the functional investigation of the GnRH pulse generator. Understanding the nature and function of the GnRH pulse generator can greatly inform a wide range of clinical studies investigating infertility treatments.
Topics: Animals; Gonadotropin-Releasing Hormone; Luteinizing Hormone; Hypothalamus; Neurokinin B; Dynorphins; Kisspeptins; Arcuate Nucleus of Hypothalamus; Mammals
PubMed: 38085702
DOI: 10.1530/JME-23-0079 -
International Journal of Molecular... Nov 2023Kisspeptin, a neuropeptide encoded by the gene, combines with its receptor Kiss1R to regulate the onset of puberty and male fertility by the...
Kisspeptin, a neuropeptide encoded by the gene, combines with its receptor Kiss1R to regulate the onset of puberty and male fertility by the hypothalamic-pituitary-gonadal axis. However, little is known regarding the expression signatures and molecular functions of in the testis. H&E staining revealed that well-arranged spermatogonia, spermatocytes, round and elongated spermatids, and spermatozoa, were observed in 4-, 6-, and 8-month-old testes compared to 1- and 3-month-old testes of Hezuo pigs; however, these were not observed in Landrance until 6 months. The diameter, perimeter, and cross-sectional area of seminiferous tubules and the perimeter and area of the tubular lumen increased gradually with age in both pigs. Still, Hezuo pigs grew faster than Landrance. The cloning results suggested that the Hezuo pigs' CDS region is 417 bp in length, encodes 138 amino acids, and is highly conserved in the kisspeptin-10 region. qRT-PCR and Western blot indicated that the expression trends of mRNA and protein were essentially identical, with higher expression levels at post-pubertal stages. Immunohistochemistry demonstrated that the Kiss1 protein was mainly located in Leydig cells and post-pubertal spermatogenic cells, ranging from round spermatids to spermatozoa. These studies suggest that Kiss1 is an essential regulator in the onset of puberty and spermatogenesis of boars.
Topics: Male; Animals; Swine; Testis; Kisspeptins; Sexual Maturation; Spermatids; Reproduction
PubMed: 38069021
DOI: 10.3390/ijms242316700 -
The Journal of Endocrinology Feb 2024During pregnancy the maternal pancreatic islets of Langerhans undergo adaptive changes to compensate for gestational insulin resistance. The lactogenic hormones are well...
During pregnancy the maternal pancreatic islets of Langerhans undergo adaptive changes to compensate for gestational insulin resistance. The lactogenic hormones are well established to play a key role in regulating the islet adaptation to pregnancy, and one of the mechanisms through which they act is through upregulating β-cell serotonin production. During pregnancy islet serotonin levels are significantly elevated, where it is released from the β-cells to drive the adaptive response through paracrine and autocrine effects. We have previously shown that placental kisspeptin (KP) also plays a role in promoting the elevated insulin secretion and β-cell proliferation observed during pregnancy, although the precise mechanisms involved are unclear. In the present study we investigated the effects of KP on expression of pro-proliferative genes and serotonin biosynthesis within rodent islets. Whilst KP had limited effect on pro-proliferative gene expression at the time points tested, KP did significantly stimulate expression of the serotonin biosynthesis enzyme Tph-1. Furthermore, the islets of pregnant β-cell-specific GPR54 knockdown mice were found to contain significantly fewer serotonin-positive β-cells when compared to pregnant controls. Our previous studies suggested that reduced placental kisspeptin production, with consequent impaired kisspeptin-dependent β-cell compensation, may be a factor in the development of GDM in humans. These current data suggest that, similar to the lactogenic hormones, KP may also contribute to serotonin biosynthesis and subsequent islet signalling during pregnancy. Furthermore, upregulation of serotonin biosynthesis may represent a common mechanism through which multiple signals might influence the islet adaptation to pregnancy.
Topics: Humans; Pregnancy; Mice; Female; Animals; Kisspeptins; Insulin; Serotonin; Placenta; Insulin-Secreting Cells; Islets of Langerhans; Prolactin
PubMed: 37997938
DOI: 10.1530/JOE-23-0218 -
Scientific Reports Nov 2023The gonadotropin-releasing hormone (GnRH) pulse and surge are considered to be generated by arcuate kisspeptin/neurokinin B/dynorphin A (KNDy) neurons and anteroventral...
The gonadotropin-releasing hormone (GnRH) pulse and surge are considered to be generated by arcuate kisspeptin/neurokinin B/dynorphin A (KNDy) neurons and anteroventral periventricular nucleus (AVPV) kisspeptin neurons, respectively, in female rodents. The majority of KNDy and AVPV kisspeptin neurons express κ-opioid receptors (KORs, encoded by Oprk1) in female rodents. Thus, this study aimed to investigate the effect of a conditional Oprk1-dependent Kiss1 deletion in kisspeptin neurons on the luteinizing hormone (LH) pulse/surge and fertility using Kiss1-floxed/Oprk1-Cre rats, in which Kiss1 was deleted in cells expressing or once expressed the Oprk1/Cre. The Kiss1-floxed/Oprk1-Cre female rats, with Kiss1 deleted in a majority of KNDy neurons, showed normal puberty while having a one-day longer estrous cycle and fewer pups than Kiss1-floxed controls. Notably, ovariectomized (OVX) Kiss1-floxed/Oprk1-Cre rats showed profound disruption of LH pulses in the presence of a diestrous level of estrogen but showed apparent LH pulses without estrogen treatment. Furthermore, Kiss1-floxed/Oprk1-Cre rats, with Kiss1 deleted in approximately half of AVPV kisspeptin neurons, showed a lower peak of the estrogen-induced LH surge than controls. These results suggest that arcuate and AVPV kisspeptin neurons expressing or having expressed Oprk1 have a role in maintaining normal GnRH pulse and surge generation, the normal length of the estrous cycle, and the normal offspring number in female rats.
Topics: Rats; Female; Animals; Kisspeptins; Luteinizing Hormone; Estrogens; Gonadotropin-Releasing Hormone; Neurokinin B; Dynorphins; Neurons; Arcuate Nucleus of Hypothalamus
PubMed: 37993510
DOI: 10.1038/s41598-023-47222-5 -
GeroScience Apr 2024The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of...
The prevalence of chronic kidney disease (CKD) is increasing globally, especially in elderly patients. Uremic cardiomyopathy is a common cardiovascular complication of CKD, characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and fibrosis. Kisspeptins and their receptor, KISS1R, exert a pivotal influence on kidney pathophysiology and modulate age-related pathologies across various organ systems. KISS1R agonists, including kisspeptin-13 (KP-13), hold promise as novel therapeutic agents within age-related biological processes and kidney-related disorders. Our investigation aimed to elucidate the impact of KP-13 on the trajectory of CKD and uremic cardiomyopathy. Male Wistar rats (300-350 g) were randomized into four groups: (I) sham-operated, (II) 5/6 nephrectomy-induced CKD, (III) CKD subjected to a low dose of KP-13 (intraperitoneal 13 µg/day), and (IV) CKD treated with a higher KP-13 dose (intraperitoneal 26 µg/day). Treatments were administered daily from week 3 for 10 days. After 13 weeks, KP-13 increased systemic blood pressure, accentuating diastolic dysfunction's echocardiographic indicators and intensifying CKD-associated markers such as serum urea levels, glomerular hypertrophy, and tubular dilation. Notably, KP-13 did not exacerbate circulatory uremic toxin levels, renal inflammation, or fibrosis markers. In contrast, the higher KP-13 dose correlated with reduced posterior and anterior wall thickness, coupled with diminished cardiomyocyte cross-sectional areas and concurrent elevation of inflammatory (Il6, Tnf), fibrosis (Col1), and apoptosis markers (Bax/Bcl2) relative to the CKD group. In summary, KP-13's influence on CKD and uremic cardiomyopathy encompassed heightened blood pressure and potentially activated inflammatory and apoptotic pathways in the left ventricle.
Topics: Humans; Rats; Animals; Male; Aged; Kisspeptins; Receptors, Kisspeptin-1; Rats, Wistar; Renal Insufficiency, Chronic; Cardiomyopathies; Hypertension; Fibrosis
PubMed: 37987885
DOI: 10.1007/s11357-023-01017-8 -
Endocrinology Nov 2023The mechanism by which arcuate kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to drive...
The mechanism by which arcuate kisspeptin (ARNKISS) neurons co-expressing glutamate, neurokinin B, and dynorphin intermittently synchronize their activity to drive pulsatile hormone secretion remains unclear in females. In order to study spontaneous synchronization within the ARNKISS neuron network, acute brain slices were prepared from adult female Kiss1-GCaMP6 mice. Analysis of both spontaneous synchronizations and those driven by high frequency stimulation of individual ARNKISS neurons revealed that the network exhibits semi-random emergent excitation dependent upon glutamate signaling through AMPA receptors. No role for NMDA receptors was identified. In contrast to male mice, ongoing tachykinin receptor tone within the slice operated to promote spontaneous synchronizations in females. As previously observed in males, we found that ongoing dynorphin transmission in the slice did not contribute to synchronization events. These observations indicate that a very similar AMPA receptor-dependent mechanism underlies ARNKISS neuron synchronizations in the female mouse supporting the "glutamate two-transition" model for kisspeptin neuron synchronization. However, a potentially important sex difference appears to exist with a more prominent facilitatory role for tachykinin transmission in the female.
Topics: Mice; Female; Male; Animals; Kisspeptins; Dynorphins; Arcuate Nucleus of Hypothalamus; Neurokinin B; Brain; Neurons; Glutamates; Gonadotropin-Releasing Hormone
PubMed: 37936337
DOI: 10.1210/endocr/bqad167