scholarly journals Arcuate Kisspeptin/Neurokinin B/Dynorphin (KNDy) Neurons Mediate the Estrogen Suppression of Gonadotropin Secretion and Body Weight

Endocrinology ◽  
2012 ◽  
Vol 153 (6) ◽  
pp. 2800-2812 ◽  
Author(s):  
Melinda A. Mittelman-Smith ◽  
Hemalini Williams ◽  
Sally J. Krajewski-Hall ◽  
Josephine Lai ◽  
Philippe Ciofi ◽  
...  
Keyword(s):  
Body Weight ◽  
Arcuate Nucleus ◽  
Estrogen Receptor Α ◽  
Neurokinin B ◽  
Abdominal Girth ◽  
Gonadotropin Secretion ◽  
Serum Lh ◽  
17Β Estradiol ◽  
Neurokinin 3 Receptor ◽  
Kndy Neurons

Estrogen withdrawal increases gonadotropin secretion and body weight, but the critical cell populations mediating these effects are not well understood. Recent studies have focused on a subpopulation of hypothalamic arcuate neurons that coexpress estrogen receptor α, neurokinin 3 receptor (NK3R), kisspeptin, neurokinin B, and dynorphin for the regulation of reproduction. To investigate the function of kisspeptin/neurokinin B/dynorphin (KNDy) neurons, a novel method was developed to ablate these cells using a selective NK3R agonist conjugated to the ribosome-inactivating toxin, saporin (NK3-SAP). Stereotaxic injections of NK3-SAP in the arcuate nucleus ablated KNDy neurons, as demonstrated by the near-complete loss of NK3R, NKB, and kisspeptin-immunoreactive (ir) neurons and depletion of the majority of arcuate dynorphin-ir neurons. Selectivity was demonstrated by the preservation of proopiomelanocortin, neuropeptide Y, and GnRH-ir elements in the arcuate nucleus and median eminence. In control rats, ovariectomy (OVX) markedly increased serum LH, FSH, and body weight, and these parameters were subsequently decreased by treatment with 17β-estradiol. KNDy neuron ablation prevented the rise in serum LH after OVX and attenuated the rise in serum FSH. KNDy neuron ablation did not completely block the suppressive effects of E2 on gonadotropin secretion, a finding consistent with redundant pathways for estrogen negative feedback. However, regardless of estrogen status, KNDy-ablated rats had lower levels of serum gonadotropins compared with controls. Surprisingly, KNDy neuron ablation prevented the dramatic effects of OVX and 17β-estradiol (E2) replacement on body weight and abdominal girth. These data provide evidence that arcuate KNDy neurons are essential for tonic gonadotropin secretion, the rise in LH after removal of E2, and the E2 modulation of body weight.

scholarly journals Ablation of KNDy Neurons Results in Hypogonadotropic Hypogonadism and Amplifies the Steroid-Induced LH Surge in Female Rats

Endocrinology ◽  
2016 ◽  
Vol 157 (5) ◽  
pp. 2015-2027 ◽  
Author(s):  
Melinda A. Mittelman-Smith ◽  
Sally J. Krajewski-Hall ◽  
Nathaniel T. McMullen ◽  
Naomi E. Rance
Keyword(s):  
Arcuate Nucleus ◽  
Hypogonadotropic Hypogonadism ◽  
Reproductive Function ◽  
Female Rats ◽  
Lh Surge ◽  
Serum Lh ◽  
Estrous Cyclicity ◽  
17Β Estradiol ◽  
Neurokinin 3 Receptor ◽  
Kndy Neurons

Abstract In the human infundibular (arcuate) nucleus, a subpopulation of neurons coexpress kisspeptin and neurokinin B (NKB), 2 peptides required for normal reproductive function. A homologous group of neurons exists in the arcuate nucleus of rodents, termed KNDy neurons based on the coexpression of kisspeptin, NKB, and dynorphin. To study their function, we recently developed a method to selectively ablate KNDy neurons using NK3-SAP, a neurokinin 3 receptor agonist conjugated to saporin (SAP). Here, we ablated KNDy neurons in female rats to determine whether these neurons are required for estrous cyclicity and the steroid induced LH surge. NK3-SAP or Blank-SAP (control) was microinjected into the arcuate nucleus using stereotaxic surgery. After monitoring vaginal smears for 3–4 weeks, rats were ovariectomized and given 17β-estradiol and progesterone in a regimen that induced an afternoon LH surge. Rats were killed at the time of peak LH levels, and brains were harvested for NKB and dual labeled GnRH/Fos immunohistochemistry. In ovary-intact rats, ablation of KNDy neurons resulted in hypogonadotropic hypogonadism, characterized by low levels of serum LH, constant diestrus, ovarian atrophy with increased follicular atresia, and uterine atrophy. Surprisingly, the 17β-estradiol and progesterone-induced LH surge was 3 times higher in KNDy-ablated rats. Despite the marked increase in the magnitude of the LH surge, the number of GnRH or anterior ventral periventricular nucleus neurons expressing Fos was not significantly different between groups. Our studies show that KNDy neurons are essential for tonic levels of serum LH and estrous cyclicity and may play a role in limiting the magnitude of the LH surge.

scholarly journals SUN-LB54 Nutritionally-Induced Alteration in KNDy Neuronal Expression in the Arcuate Nucleus of Ewes

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ligia D Prezotto ◽  
Clay A Lents ◽  
Dale A Redmer ◽  
Anna T Grazul-Bilska ◽  
Jennifer F Thorson
Keyword(s):  
Body Weight ◽  
Energy Balance ◽  
Estrous Cycle ◽  
Luteal Phase ◽  
Arcuate Nucleus ◽  
Pulse Amplitude ◽  
Domestic Animal ◽  
Neurokinin B ◽  
Lh Pulsatility ◽  
Kndy Neurons

Abstract Kisspeptin, neurokinin B, and dynorphin are imperative for GnRH/LH pulsatility and reproductive cyclicity. Neurons co-expressing these neuropeptides, KNDy neurons, within the arcuate nucleus of the hypothalamus (ARC) are positioned to integrate energy balance signals from neuronal and glial cells. Energy balance mediates neurokinin B expression in the ARC and LH pulse amplitude. Dynorphin mediates progesterone negative feedback on GnRH neurons. The hypothesis that the number of KNDy-expressing neurons in the ARC of ewes during the luteal phase of the estrous cycle is influenced by energy balance was tested using ovary-intact, mature ewes fed to lose, maintain, or gain body weight. Fluorescent multiplex immunohistochemistry was employed to identify and quantify neurons expressing a single neuropeptide and co-expressing kisspeptin, neurokinin B, and dynorphin in the ARC. Kaminski et al. (1) reported previously that concentrations of insulin and leptin differed between ewes fed to achieve different body weights and that ewes fed to gain body weight had increased concentrations of progesterone in the luteal phase of the estrous cycle. Moreover, tanycyte density and cellular penetration into the ARC are increased in ewes fed to gain body weight (2). Number of neurons in the ARC expressing kisspeptin (14.9 ± 2.7 neurons, 20.9 ± 3.6 neurons, and 51.5 ± 3.3 neurons in ewes fed to lose, maintain, and gain body weight, respectively), neurokinin B (21.5 ± 3.2 neurons, 31.3 ± 4.3 neurons, and 56.0 ± 3.9 neurons in ewes fed to lose, maintain, and gain body weight, respectively), and dynorphin (10.1 ± 2.4 neurons, 14.9 ± 3.2 neurons, and 33.1 ± 2.9 neurons in ewes fed to lose, maintain, and gain body weight, respectively) protein was increased (P < 0.0001) in ewes fed to gain body weight. Number of KNDy neurons in the ARC expressing kisspeptin, neurokinin B, and dynorphin protein was decreased in ewes fed to lose body weight (1.0 ± 0.5 neurons; P = 0.01) and increased in ewes fed to gain body weight (6.7 ± 0.6 neurons; P = 0.0005) when compared to ewes fed to maintain body weight (3.3 ± 0.7 neurons). These findings suggest that expression of kisspeptin, neurokinin B, and dynorphin protein in the ARC during the luteal phase of the estrous cycle may be influenced by nutritionally-induced alterations in circulating concentrations of progesterone that drive changes in morphology and density of tanycytes. Moreover, these results demonstrate that changes in KNDy neurons within the ARC occur as an adaptation to energy balance, potentially regulated divergently by metabolic milieu. References: (1) Kaminski et al., Theriogenology. 2015 83:808-16. (2) Prezotto et al., Domestic Animal Endocrinology. 2020 Accepted.

scholarly journals The Inhibitory Effects of Neurokinin B on GnRH Pulse Generator Frequency in the Female Rat

Endocrinology ◽  
2012 ◽  
Vol 153 (1) ◽  
pp. 307-315 ◽  
Author(s):  
James S. Kinsey-Jones ◽  
Pasha Grachev ◽  
Xiao Feng Li ◽  
Yuan Shao Lin ◽  
Stuart R. Milligan ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Pulse Generator ◽  
Female Rat ◽  
Neurokinin B ◽  
Gonadotropin Secretion ◽  
Multiunit Activity ◽  
Ovx Rats ◽  
17Β Estradiol ◽  
Neurokinin 3 Receptor

Neurokinin B (NKB) and its receptor (neurokinin-3 receptor) are coexpressed with kisspeptin and dynorphin A (Dyn) within neurons of the hypothalamic arcuate nucleus, the suggested site of the GnRH pulse generator. It is thought that these neuropeptides interact to regulate gonadotropin secretion. Using the ovariectomized (OVX) and OVX 17β-estradiol-replaced rat models, we have carried out a series of in vivo neuropharmacological and electrophysiological experiments to elucidate the hierarchy between the kisspeptin, NKB, and Dyn signaling systems. Rats were implanted with intracerebroventricular cannulae and cardiac catheters for frequent (every 5 min) automated serial blood sampling. Freely moving rats were bled for 6 h, with intracerebroventricular injections taking place after a 2-h control bleeding period. A further group of OVX rats was implanted with intra-arcuate electrodes for the recording of multiunit activity volleys, which coincide invariably with LH pulses. Intracerebroventricular administration of the selective neurokinin-3 receptor agonist, senktide (100–600 pmol), caused a dose-dependent suppression of LH pulses and multiunit activity volleys. The effects of senktide did not differ between OVX and 17β-estradiol-replaced OVX animals. Pretreatment with a selective Dyn receptor (κ opioid receptor) antagonist, norbinaltorphimine (6.8 nmol), blocked the senktide-induced inhibition of pulsatile LH secretion. Intracerebroventricular injection of senktide did not affect the rise in LH concentrations after administration of kisspeptin (1 nmol), and neither did kisspeptin preclude the senktide-induced suppression of LH pulses. These data show that NKB suppresses the frequency of the GnRH pulse generator in a Dyn/κ opioid receptor-dependent fashion.

scholarly journals KNDy Neurons Modulate the Magnitude of the Steroid-Induced Luteinizing Hormone Surges in Ovariectomized Rats

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4200-4213 ◽  
Author(s):  
Cleyde V. Helena ◽  
Natalia Toporikova ◽  
Bruna Kalil ◽  
Andrea M. Stathopoulos ◽  
Veronika V. Pogrebna ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Arcuate Nucleus ◽  
Ovariectomized Rats ◽  
Neurokinin B ◽  
Lh Surge ◽  
Neuronal Populations ◽  
Lh Release ◽  
Positive And Negative Feedback ◽  
Kndy Neurons ◽  
Lh Secretion

Kisspeptin is the most potent stimulator of LH release. There are two kisspeptin neuronal populations in the rodent brain: in the anteroventral periventricular nucleus (AVPV) and in the arcuate nucleus. The arcuate neurons coexpress kisspeptin, neurokinin B, and dynorphin and are called KNDy neurons. Because estradiol increases kisspeptin expression in the AVPV whereas it inhibits KNDy neurons, AVPV and KNDy neurons have been postulated to mediate the positive and negative feedback effects of estradiol on LH secretion, respectively. Yet the role of KNDy neurons during the positive feedback is not clear. In this study, ovariectomized rats were microinjected bilaterally into the arcuate nucleus with a saporin-conjugated neurokinin B receptor agonist for targeted ablation of approximately 70% of KNDy neurons. In oil-treated animals, ablation of KNDy neurons impaired the rise in LH after ovariectomy and kisspeptin content in both populations. In estradiol-treated animals, KNDy ablation did not influence the negative feedback of steroids during the morning. Surprisingly, KNDy ablation increased the steroid-induced LH surges, accompanied by an increase of kisspeptin content in the AVPV. This increase seems to be due to lack of dynorphin input from KNDy neurons to the AVPV as the following: 1) microinjections of a dynorphin antagonist into the AVPV significantly increased the LH surge in estradiol-treated rats, similar to KNDy ablation, and 2) intra-AVPV microinjections of dynorphin in KNDy-ablated rats restored LH surge levels. Our results suggest that KNDy neurons provide inhibition to AVPV kisspeptin neurons through dynorphin and thus regulate the amplitude of the steroid-induced LH surges.

scholarly journals Disparate Changes in Kisspeptin and Neurokinin B Expression in the Arcuate Nucleus After Sex Steroid Manipulation Reveal Differential Regulation of the Two KNDy Peptides in Rats

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 3945-3955 ◽  
Author(s):  
Agnete Overgaard ◽  
Francisco Ruiz-Pino ◽  
Juan M. Castellano ◽  
Manuel Tena-Sempere ◽  
Jens D. Mikkelsen
Keyword(s):  
Sex Steroids ◽  
Arcuate Nucleus ◽  
Detailed Examination ◽  
Differential Regulation ◽  
Sex Steroid ◽  
Neurokinin B ◽  
Regulated Expression ◽  
Male Sex ◽  
Specific Regulation ◽  
Kndy Neurons

Abstract Kisspeptin, neurokinin B (NKB) and dynorphin A are coexpressed in a population of neurons in the arcuate nucleus (ARC), termed KNDy neurons, which were recently recognized as important elements for the generation of GnRH pulses. However, the topographic distribution of these peptides and their regulated expression by sex steroids are still not well understood. In this study, detailed examination of NKB and kisspeptin immunoreactivity in the rat ARC was carried out, including comparison between sexes, with and without sex steroid replacement. Neurons expressing kisspeptin and NKB were more prominent in the caudal ARC of females, whereas neurons expressing NKB, but not kisspeptin, were the most abundant in the male. Sex steroid manipulation revealed differential regulation of kisspeptin and NKB; although kisspeptin immunoreactive (ir) cells increased in response to gonadectomy, NKB remained unchanged. Furthermore, the number of NKB-ir cells increased upon sex steroid replacement compared with gonadectomy, whereas kisspeptin did not, suggesting that sex steroids differently regulate these peptides. In addition, only in females did the density of kisspeptin- and NKB-ir fibers in the ARC increase upon sex steroid replacement in relation to sham and ovariectomy, respectively, suggesting sex-specific regulation of release. In conclusion, our observations reveal sex differences in the number of kisspeptin- and NKB-ir cells, which are more prominent in the caudal ARC. The divergent regulation of kisspeptin and NKB peptide contents in the ARC as a function of sex and steroid milieu enlarge our understanding on how these neuropeptides are posttranscriptionally regulated in KNDy neurons.

scholarly journals Neurokinin 3 receptor antagonism ameliorates key metabolic features in a hyperandrogenic PCOS mouse model

Endocrinology ◽  
2021 ◽  
Author(s):  
Irene E Sucquart ◽  
Ruchi Nagarkar ◽  
Melissa C Edwards ◽  
Valentina Rodriguez Paris ◽  
Ali Aflatounian ◽  
...  
Keyword(s):  
Body Weight ◽  
Mouse Model ◽  
Polycystic Ovary ◽  
Serum Triglyceride ◽  
Total Body Weight ◽  
Neurokinin B ◽  
Glucose Levels ◽  
Neurokinin 3 Receptor ◽  
Total Body ◽  
Novel Therapeutic Strategies

Abstract Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterised by a range of endocrine, reproductive and metabolic abnormalities. At present, management of women with PCOS is suboptimal as treatment is only symptomatic. Clinical and experimental advances in our understanding of PCOS etiology support a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. Hyperandrogenism is a key PCOS trait and androgen actions play a role in regulating the kisspeptin-/neurokinin B-/dynorphin (KNDy) system. This study aimed to investigate if targeted antagonism of neurokinin B signalling through the neurokinin 3 receptor (NK3R) would reverse PCOS traits in a dihydrotestosterone (DHT)-induced mouse model of PCOS. After 3 months, DHT exposure induced key reproductive PCOS traits of cycle irregularity and ovulatory dysfunction, and PCOS-like metabolic traits including increased body weight; white and brown fat pad weights; fasting serum triglyceride and glucose levels and blood glucose iAUC. Treatment with a NK3R antagonist (MLE4901) did not impact the observed reproductive defects. In contrast, following NK3R antagonist treatment, PCOS-like females displayed decreased total body weight, adiposity and adipocyte hypertrophy, but increased respiratory exchange ratio, suggesting NK3R antagonism altered the metabolic status of the PCOS-like females. NK3R antagonism did not improve circulating serum triglyceride or fasted glucose levels. Collectively, these findings demonstrate that NK3R antagonism may be beneficial in the treatment of adverse metabolic features associated with PCOS and support neuroendocrine targeting in the development of novel therapeutic strategies for PCOS.

scholarly journals Prenatal Testosterone Treatment Leads to Changes in the Morphology of KNDy Neurons, Their Inputs, and Projections to GnRH Cells in Female Sheep

Endocrinology ◽  
2015 ◽  
Vol 156 (9) ◽  
pp. 3277-3291 ◽  
Author(s):  
Maria Cernea ◽  
Vasantha Padmanabhan ◽  
Robert L. Goodman ◽  
Lique M. Coolen ◽  
Michael N. Lehman
Keyword(s):  
Feedback Control ◽  
Arcuate Nucleus ◽  
Preoptic Area ◽  
Neurokinin B ◽  
Medial Basal Hypothalamus ◽  
Synaptic Inputs ◽  
Prenatal Testosterone ◽  
Peptide Expression ◽  
Kndy Neurons ◽  
Female Sheep

Prenatal testosterone (T)-treated ewes display a constellation of reproductive defects that closely mirror those seen in PCOS women, including altered hormonal feedback control of GnRH. Kisspeptin/neurokinin B/dynorphin (KNDy) neurons of the arcuate nucleus (ARC) play a key role in steroid feedback control of GnRH secretion, and prenatal T treatment in sheep causes an imbalance of KNDy peptide expression within the ARC. In the present study, we tested the hypothesis that prenatal T exposure, in addition to altering KNDy peptides, leads to changes in the morphology and synaptic inputs of this population, kisspeptin cells of the preoptic area (POA), and GnRH cells. Prenatal T treatment significantly increased the size of KNDy cell somas, whereas POA kisspeptin, GnRH, agouti-related peptide, and proopiomelanocortin neurons were each unchanged in size. Prenatal T treatment also significantly reduced the total number of synaptic inputs onto KNDy neurons and POA kisspeptin neurons; for KNDy neurons, the decrease was partly due to a decrease in KNDy-KNDy synapses, whereas KNDy inputs to POA kisspeptin cells were unaltered. Finally, prenatal T reduced the total number of inputs to GnRH cells in both the POA and medial basal hypothalamus, and this change was in part due to a decreased number of inputs from KNDy neurons. The hypertrophy of KNDy cells in prenatal T sheep resembles that seen in ARC kisspeptin cells of postmenopausal women, and together with changes in their synaptic inputs and projections to GnRH neurons, may contribute to defects in steroidal control of GnRH observed in this animal model.

scholarly journals Evidence That Dynorphin Acts Upon KNDy and GnRH Neurons During GnRH Pulse Termination in the Ewe

Endocrinology ◽  
2018 ◽  
Vol 159 (9) ◽  
pp. 3187-3199 ◽  
Author(s):  
Peyton W Weems ◽  
Lique M Coolen ◽  
Stanley M Hileman ◽  
Steven Hardy ◽  
Rick B McCosh ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Third Ventricle ◽  
Pulse Generation ◽  
G Protein Coupled Receptors ◽  
Neurokinin B ◽  
Gnrh Secretion ◽  
Pulsatile Gnrh ◽  
Gnrh Neurons ◽  
Kndy Neurons ◽  
G Protein Coupled

Abstract A subpopulation of neurons located within the arcuate nucleus, colocalizing kisspeptin, neurokinin B, and dynorphin (Dyn; termed KNDy neurons), represents key mediators of pulsatile GnRH secretion. The KNDy model of GnRH pulse generation proposes that Dyn terminates each pulse. However, it is unknown where and when during a pulse that Dyn is released to inhibit GnRH secretion. Dyn acts via the κ opioid receptor (KOR), and KOR is present in KNDy and GnRH neurons in sheep. KOR, similar to other G protein–coupled receptors, are internalized after exposure to ligand, and thus internalization can be used as a marker of endogenous Dyn release. Thus, we hypothesized that KOR will be internalized at pulse termination in both KNDy and GnRH neurons. To test this hypothesis, GnRH pulses were induced in gonad-intact anestrous ewes by injection of neurokinin B (NKB) into the third ventricle and animals were euthanized at times of either pulse onset or termination. NKB injections produced increased internalization of KOR within KNDy neurons during both pulse onset and termination. In contrast, KOR internalization into GnRH neurons was seen only during pulse termination, and only in GnRH neurons within the mediobasal hypothalamus (MBH). Overall, our results indicate that Dyn is released onto KNDy cells at the time of pulse onset, and continues to be released during the duration of the pulse. In contrast, Dyn is released onto MBH GnRH neurons only at pulse termination and thus actions of Dyn upon KNDy and GnRH cell bodies may be critical for pulse termination.

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