Unlocking Therapeutic Potential: Kisspeptin & Neurokinin B

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Kisspeptin (KP) and neurokinin B (NKB) regulate the reproductive endocrine axis by influencing GnRH activity and secretion. Inactivating variants in KP or NKB signaling can lead to hypogonadotropic hypogonadism and pubertal development failure. KP and NKB offer potential therapeutic applications in various health conditions, including pregnancy, metabolic, liver, bone, and behavioral disorders. NKB antagonism may help manage menopausal hot flashes and reproductive disorders like PCOS, uterine fibroids, and endometriosis. The review presents an up-to-date overview of the data supporting the development of diagnostic and therapeutic uses of KP and NKB.



Kisspeptin in healthy men

*Kisspeptin (KP-54) administration in healthy men led to
dose-dependent rises in LH and FSH.

*KP-54 infusion (0.24 nmol/kg/hr) increased mean LH levels 2.6-fold higher than placebo.

*KP-10 (0.77 nmol/kg) IV bolus strongly stimulated LH secretion, with continuous infusion (3.07 nmol/kg/hr) leading to persistent LH secretion over 22.5 hrs.

*In direct comparison, GnRH elicited greater LH and FSH responses than KP-54 and KP-10.

*KP-10 increased LH pulse frequency and reset the 'GnRH pulse generator' in healthy men but not women.

*KP-10 induced an LH pulse, increased LH pulse amplitude by 2.4-fold, and delayed the subsequent pulse, resetting the pulse schedule.




Kisspeptin in healthy women

*KP-54 administration in healthy premenopausal women increased LH during all menstrual cycle phases, with the highest levels during the pre-ovulatory phase.

*KP-10 increased gonadotropins during the preovulatory phase but was least sensitive during the follicular phase.

*KP-54 can still increase LH pulsatility during the follicular phase in premenopausal women.

*Chronic KP administration increased LH during different phases of the menstrual cycle.

*KP receptor analogs, like MVT-602, generate similar LH responses, but the peak LH level occurs later than KP-54, resulting in a four-fold increase in the AUC of LH secretion.




Neurokinin B in healthy men and women

*NKB administration increased LH concentration in male juvenile monkeys but did not significantly affect LH, FSH, or testosterone in healthy men during IV infusions.

*Healthy premenopausal women also showed no significant differences in LH pulsatility or hormone levels with NKB IV infusion.

*NKB induced vasoactive effects in both healthy men and premenopausal women, suggesting its potential for managing vasomotor symptoms in postmenopausal women and cancer therapy.

*Safe and effective NKB receptor antagonists, mainly NK3R, have been investigated for this purpose, and NK1R antagonists may have a therapeutic role in breast and lung cancer treatment.




Kisspeptin (KP) and neurokinin B (NKB) play crucial roles in regulating the reproductive endocrine axis and gonadotropin-releasing hormone (GnRH) activity. KP has diagnostic potential for pubertal and pregnancy-related disorders. It could be utilized in diagnosing central precocious puberty and predicting pregnancy complications. Elevated KP levels in metabolic fatty liver disease indicate its potential as a marker for discriminating patients. KP-based therapies show promise for restoring reproductive function and inducing oocyte maturation in IVF. KP agonists could alleviate hepatic steatosis and fibrosis, and enhance bone metabolism, making them a potential therapy for NAFLD and osteoporosis. KP also has therapeutic potential for psychosexual dysfunctions.

 

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FIGURE 1: Kisspeptin and neurokinin B in the regulation of the hypothalamic-pituitary-gonadal (HPG) axis
Kisspeptin (KP) is released from the Preoptic Area (POA) (equivalent to the rostral periventricular area of the third ventricle, RP3V, in non-humans) and infundibular nucleus (arcuate, ARC, nucleus in non-humans) of the hypothalamus. The KP neurons in the infundibular nucleus co-express neurokinin B (NKB) and dynorphin (known as KNDy neurons) and are involved in the auto synaptic regulation of pulsatile KP secretion via the NKB receptor (NK3R) and kappa opioid peptide receptor (KOR) respectively. Dynorphin inhibits, whereas NKB stimulates KP release Following KP's release from the hypothalamus, KP stimulates the hypothalamic gonadotropin-releasing hormone (GnRH) neurons to release GnRH in a pulsatile manner, which stimulates anterior pituitary production of gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH)) and subsequent production of gonadal (testicular/ovarian) sex-steroids (Estrogen; E2, Testosterone; T). The gonadotropins’ effect on the ovary stimulates follicular development, oocyte maturation, and ovulation. The KNDy neurons in the infundibular nucleus mainly receive negative feedback (red) (E2, T) from sex steroids, whereas KP neurons in the preoptic area receive positive feedback from estrogen in females (green) (high E2), which is involved in the preovulatory LH surge. Sex-steroid communication with the pre-optic area has not yet been fully established in males.

Abbreviations: Kisspeptin’ KP, Neurokinin B; NKB, Follicle Stimulating Hormone; FSH, Gonadotropin-Releasing Hormone; GnRH, Kisspeptin receptor; KISS1R, kappa opioid peptide receptor; KOR, Luteinizing Hormone; LH, Neurokinin 3 receptor; NK3R, Estrogen; E, Progesterone; P, Rostral periventricular area of the third ventricle; RP3V, Testosterone; T, Preoptic Area; POA. Figure created with BioRender.com

 

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FIGURE 2: KISS1 and KISS1R human gene expression in areas where kisspeptin signaling has well-identified roles
Expression is abundant in other areas of the human body, not illustrated in Figure 2, in which the full role of kisspeptin (KP)-signaling has yet to be elucidated. This widespread distribution of KISS1 and KISS1R reflects the pleiotropic action of KP, beyond reproduction. In humans, the tissue distribution of KISS1 and KISS1R has been identified using RT-PCR methods. KISS1 mRNA is predominantly expressed in the placenta, with the next highest level in the testis, and moderate levels in the pancreas, liver, uterus, gonads, and small intestine). KISS1 mRNA is also strongly expressed in bone, in particular the osteoblasts. KISS1R expression is particularly abundant in the placenta, pituitary, spinal cord, liver, pancreas, and bone (osteoblasts and osteoclasts), but expressed at lower levels in other tissues, such as the stomach, uterus, small intestine, thymus, spleen, lung, gonads, heart, kidney, adrenal gland, bone, and fetal liver. Both KISS1 and KISS1R are also expressed in the brain, and in particular the human hypothalamus, as well as extra-hypothalamic regions, such as the amygdala, caudate nucleus, cerebellum, cingulate gyrus, globus pallidus, hippocampus, medial frontal gyrus, nucleus accumbens, para-hippocampal gyrus, putamen, spinal cord, striatum, substantia nigra, superior frontal gyrus and thalamus, as localized by RT-PCR.

Abbreviations: KISS1; kisspeptin gene, KISS1R; kisspeptin receptor gene, reverse transcription polymerase chain reaction; RT-PCR. Figure created with BioRender.com

 

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FIGURE 3: Kisspeptin receptor induces differential responses in downstream signaling
Kisspeptin (KP) has a high-affinity binding site for the human KP receptor and induces a biphasic response in downstream signaling, with an acute (lasting ~5 min) and prolonged response (lasting >30 minutes). KISS1R (coupled to Gαq/11) triggers the activation of phospholipase C (PLC) and subsequent recruitment of secondary intracellular messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which in turn mediate intracellular calcium release. DAG additionally activates protein kinase C (PKC) and induces downstream phosphorylation of extracellular signal-related kinase (ERK) 1 and 2. Kisspeptin binding results in the recruitment of β-arrestin and GPCR serine/threonine kinases (GRK2) which leads to desensitization and internalization of the kisspeptin receptor (through uncoupling of Gαq/11). β-arrestin traffics the desensitized KISS1R to the clathrin-coated pit resulting in sequestration which results in β-arrestin-dependent signaling. Internalized KISS1R eventually dissociates from β-arrestin and the majority of kisspeptin receptors become resensitized and traffic back to the cell surface, thus maintaining a continuous pool of receptors at the cell surface which are ready to signal while a lesser population of KISS1R are targeted for degradation.

Abbreviations: KISS1R; kisspeptin receptor gene, PLC; phospholipase C, IP3; inositol triphosphate, DAG; diacylglycerol, PKC; protein kinase C, ERK; extracellular signal-related kinase, GRK2; GPCR serine/threonine kinases. Figure created with BioRender.com

 

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FIGURE 4: Role of kisspeptin in disorders of puberty
Puberty is triggered by the pulsatile secretion of gonadotropin-releasing hormone (GnRH) and subsequent downstream activation of the hypothalamic-pituitary-gonadal (HPG) reproductive axis. The pulsatile secretion of GnRH requires adequate development and migration of GnRH neurons from the olfactory bulb to the hypothalamus. The HPG axis is transiently activated at two distinct phases; during early developmental life, termed ‘mini puberty’, and at the onset of puberty. Kisspeptin (KP) stimulates an LH response during the later stages of puberty (Tanner stage 5) thus suggesting KISS1R sensitivity on GnRH neurons develops during the later part of puberty. KISS1 gain in function variants can lead to premature activation of the HPG axis resulting in early central precocious puberty (CPP). Kisspeptin (KP) levels are increased in CPP versus age-matched healthy controls and thus KP has the potential in aiding in the diagnosis of early puberty. KISS1 loss in function variants causes aberrations in GnRH neuronal development or migration and impairs GnRH secretion resulting in congenital hypogonadotropic hypogonadism (CHH) and delay puberty. Constitutional delay of growth and puberty (CDGP) is another common cause of delayed puberty and can be challenging to accurately differentiate from CHH. Kisspeptin (KP), a potent stimulator of GnRH and luteinizing hormone (LH) release, induces differential responses in CDGP (increased LH) and CHH (absent/ reduced LH) and thus can aid in the diagnosis of delayed puberty.

Abbreviations: Gonadotropin-releasing hormone (GnRH); central precocious puberty (CPP); Kisspeptin (KP); congenital hypogonadotropic hypogonadism (CHH); Constitutional delay of growth and puberty (CDGP); luteinizing hormone (LH). Figure created with BioRender.com

 

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FIGURE 5: Therapeutic potential of kisspeptin and neurokinin B in female reproductive disorders
Activation of hypothalamic kisspeptin (KP) neurons directly stimulates gonadotropin-releasing hormone (GnRH) release and regulates reproductive hormone secretion. Absent or reduced GnRH and luteinizing hormone (LH) pulses observed in hypothalamic amenorrhea (HA) and hyperprolactinemia can be restored using exogenous KP. Whilst GnRH/ LH pulsatility is retained in patients with endometriosis/ uterine fibroids, patients with polycystic ovary syndrome (PCOS) have high pulsatility. During menopause, increased kisspeptin-neurokinin b-dynorphin (KNDy) neuronal activity results in very high GnRH/ LH pulses and induction of vasomotor symptoms through dysregulation of the thermoregulatory center. Considering NKB antagonism partially suppresses (but does not abolish) the reproductive endocrine axis, NK3R antagonists have been developed for the therapeutic potential of these disorders. NK3R antagonism can be used to treat endometriosis/ uterine fibroids (by reducing estradiol; E2), PCOS (by reducing androgens), and menopausal hot flashes (by reducing vasomotor symptoms).

Abbreviations: Kisspeptin (KP); Gonadotropin-releasing hormone (GnRH); luteinizing hormone (LH); hypothalamic amenorrhea (HA); Polycystic ovary syndrome (PCOS); kisspeptin-neurokinin b-dynorphin (KNDy); estradiol (E2). Figure created with BioRender.com

 

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FIGURE 6: The utility of kisspeptin in the prediction of pregnancy complications
Kisspeptin (KP) regulates trophoblast invasion and placentation during pregnancy and has emerged as a promising biomarker to predict several adverse pregnancy complications. The KISS1 gene is abundantly expressed in syncytiotrophoblasts, whereas its receptor (KISS1R) is expressed in both cytotrophoblasts and syncytiotrophoblasts. Circulating KP levels increase linearly in healthy pregnancies but are reduced in miscarriage during early pregnancy. KP can accurately predict the risk of miscarriage with average/ above average levels of KP being associated with a <1% risk of miscarriage. KP levels are reduced in fetal growth restriction (FGR) and gestational diabetes mellitus (GDM) and raised in pre-eclampsia (PET) during the later stages of pregnancy.

Abbreviations: Kisspeptin (KP); kisspeptin gene (KISS1); kisspeptin receptor (KISS1R); fetal 18 growth restriction (FGR); gestational diabetes mellitus (GDM), pre-eclampsia (PET). Figure 19 was created with BioRender.com

 

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FIGURE 7: Effects of liver-specific Kiss1r knockout and enhanced kisspeptin signaling
Liver-specific Kiss1r knockout mice model placed on a high-fat diet exhibited increased lipogenesis, triglyceride synthesis, and reduced mitochondrial β oxidation compared to controls. This resulted in increased triglyceride levels, serum alanine transaminase levels (indicating hepatocellular injuries), and hepatic steatosis. Increased body weight and reduced energy expenditure were observed. Higher fasting glucose and basal insulin levels, indicating glucose intolerance and insulin resistance were also observed. Moreover, markers of inflammation and early stages of fibrosis were upregulated. Effects of enhanced kisspeptin signaling: Wildtype mice were placed on a high-fat diet for 6 weeks prior to administration of MVT-602, a kisspeptin receptor agonist, for 5 weeks on a high-fat diet. MVT-602 alleviated hepatic steatosis and metabolic deterioration through improvements in insulin sensitivity, lower basal insulin levels, and reduced triglyceride and ALT levels. MVT-602 treated mice had slightly lower body weight compared to controls with increased energy expenditure in the light phase. Mechanistically MVT-602 treatment under high-fat diet conditions significantly reduced triglyceride synthesis, increased lipolysis, and mitochondrial β oxidation compared to controls. Markers of inflammation and early stages of fibrosis were downregulated.

Abbreviations: ALT, Alanine transaminase; Kiss1r, Kisspeptin receptor; TG: triglyceride. Figure 17 was created with BioRender.com

 

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FIGURE 8: The effects of kisspeptin signaling on key reproductive behaviors in rodents, sheep, and humans including olfactory processing, sexual partner preference, copulatory behavior, and arousal and bonding
Kisspeptin is widely expressed in limbic and paralimbic regions of the brain, that are involved in reproductive behaviors. Olfaction: KP expression and activity increased in several brain regions in response to opposite-sex olfactory cues in male mice and female mice and ewes. In humans, KP administration enhanced limbic brain activity when men were exposed to a pleasant feminine scent. Sexual partner preference and bonding: Studies showed that the KP MePD neurons regulate partner preferences in male mice, whereas intraperitoneal and intranasal administration of KP to male rats increases sexual motivation. When peripheral KP was administered to Kiss KO female mice, normal male-directed sexual preference was restored. In healthy heterosexual men, peripheral KP administration increased brain activity in aesthetic brain regions in response to viewing female faces. Copulatory behavior and arousal: KP stimulation in the MePD resulted in erections in male rats, whereas both peripheral and central KP administration to female mice robustly stimulated lordosis. In healthy heterosexual men, peripheral KP administration enhanced limbic brain activity when exposed to visual sexual stimuli. KP administration to males with HSDD deactivated brain regions involved in self-monitoring and introspection, and increased brain activity in sexual arousal centers, in response to watching erotic videos in the fMRI scanner. KP administration also led to increases in penile tumescence. KP administration to pre-menopausal women with HSDD, deactivated brain regions involved in inhibitory control, and activated areas 18 known to be activated in the context of sexual arousal in response to erotic visual cues.

Abbreviations: AVPV; anteroventral periventricular nucleus, fMRI; functional magnetic resonance imaging, gonadotropin-releasing hormone, KP; kisspeptin, KO; knock out, MePD; posterodorsal subnucleus of the medial amygdala, HSDD; hypoactive sexual desire disorder. Figure created with BioRender.com

 

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