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Kisspeptin Reduces Fat Formation by Inhibiting Adipogenesis and Fat Cell Differentiation.
“Kisspeptin-10: (i) inhibited cell proliferation, viability and adipogenesis in 3T3-L1 and decreased expression of PPAR-γ and CEBPβ-genes, which are involved in the differentiation processes and adipogenesis; (ii) increased lipolysis in 3T3-L1 cells and rat adipocytes by enhancing expression of periliphin and hormone-sensitive lipase; (iii) modulated glucose uptake and lipogenesis; (iv) stimulated leptin and decreased adiponectin secretion from rat adipocytes.” (1)Kisspeptin Rebuilds Bones by Activating Osteoblasts, Turning Stem Cells into Bones.
“Kisspeptin-10 (KP-10) stimulates osteoblast differentiation through GPR54-mediated regulation of BMP2 expression and activation... Osteoblast differentiation is controlled by a range of hormones and cytokines, such as bone morphogenetic protein (BMPs), and multiple transcription factors, such as Runt-related transcription factor 2 (Runx2), alkaline phosphatase (ALP), and Distal-less homeobox 5 (Dlx5). In the present study, KP-10-treatment significantly increased the expression of osteogenic genes, including mRNA and protein levels of BMP2, in C3H10T1/2 cells. Moreover, KP-10 induced BMP2-luc activity and increased phosphorylation of Smad1/5/9. In addition, NFATc4 specifically mediated KP-10-induced BMP2 gene expression. However, KP-10 treatment did not induce expression of the BMP2 and Runx2 genes in GPR54−/− cells… Taken together, these findings suggest that KP-10/GPR54 signaling induces osteoblast differentiation via NFATc4-mediated BMP2 expression.” (2)
Kisspeptin Stimulates Testosterone Top-Down, From Hypothalamus Neurons to the Testes.
“A hormone made by a part of the brain called the hypothalamus. GnRH causes the pituitary gland in the brain to make and secrete the hormones luteinizing hormone (LH) and follicle-stimulating hormone (FSH). “ (3)(4)
Hypothalamus triggers GnRH, which triggers the pituitary gland to release LH and FSH… FSH leads to testosterone release, which then blocks the hypothalamus and pituitary gland from releasing more testosterone. This is the body’s endogenous feedback loop. Kisspeptin targets the very top of it to induce activation of the entire cascade from the top-down.
(5)
“Kisspeptin (KP), a protein named after the famous chocolates 'Kisses' has revolutionized both our knowledge of hypothalamic pituitary gonadal axis (HPG) and the understanding of neuroendocrine regulation of reproduction. Kisspeptin bases on the principle of feedback which allows for the maintaining of homeostasis in various physiological states of the body. The first information about the kisspeptin protein and its influence on the function of HPG axis appeared at the end of the 20th entury during the studies on the function of dynorphin A and neurokinin B. The HPG works mainly due to the interaction and integration of brain and gonadal signals. In the rat, the estrogene’s receptor is not present on gonadotropin-releasing hormone (GnRH) neurons; consequently, gonadal feedback must be realized by the intermediate signaling pathway. The protagonist of this route is kisspeptin. Kisspeptin plays a decisive role in the control of fertility by initiating and regulating the process of puberty and pituitary secretion. Since 2005, it has been known to be the strongest activator of the HPG axis. Depriving kisspeptin or its receptor weakens fertility and reproductive physiology, while enhancement of the mutation function in the KISS1R gene results in premature maturation. In immature rats, administration of kisspeptin induced the onset of maturation, while administration of its antagonist delayed it.” (6)
No Long-Term Loss of LH or Testosterone Release in Studies of Men Using Kisspeptin-10.
"This study was designed to assess LH secretion and potential desensitization of kisspeptin-KISS1R with a continuous high-dose infusion of kisspeptin-10.”“The kisspeptin receptor KISS1R is known to desensitize rapidly in vitro, raising the possibility of rapid hypothalamic desensitization. Although such desensitization is a parsimonious explanation for the decreased response observed here, desensitization has to be occurring rapidly after kisspeptin-10 administration before maximal stimulation of gonadotrophs is achieved. Because the fast half-life of LH in healthy men is 18 min, lower peak LH after the 3 μg/kg would suggest that the gonadotroph stimulation was submaximal.”
“Despite continually infusing kisspeptin-10 for 22.5 h, we found no such desensitization, and indeed LH secretion tended to increase progressively. This is possibly a function of the dose of kisspeptin used in our study being lower than that used in the primate studies. Tachyphylaxis of LH response has been seen during the twice-daily administration of kisspeptin-54 to women with hypothalamic amenorrhea, but this occurred over a much longer time period, i.e. 2 wk." (7)
"Desensitization of gonadotropin responses to kisspeptin in the female rat: analyses of LH and FSH secretion at different developmental and metabolic states... Desensitization of LH induced testosterone release et al. can occur in women, however." (8)
“Kisspeptin resets the GnRH pulse generator in men, but does not appear to do so in women.” (9)
Effects of GnRH on the Brain.
"The effect of GH and GnRH (by independent administration) has been associated with beneficial impacts in patients with brain trauma and spinal cord injuries. Both GH and GnRH have demonstrated potent neurotrophic, neuroprotective, and neuroregenerative action."
"There is a widespread incidence of GnRH and GnRH-R immunoreactive neurons in the cerebral cortex, suggesting that GnRH may act as a common neuromodulatory peptide. The presence of a GnRH receptor and expression of its mRNA was demonstrated by immunohistochemistry and RT-PCR analysis in both cerebral cortical neurons of rat embryos and cerebral cortical tissues of adult rats. In addition, a decrease in GnRH-R mRNA expression was shown when cultured neurons of rat embryos were treated with GnRH." (10)
Kisspeptin-10 Triggers Calcium (Ca2+) Release:
“A large number of studies have indicated that the kisspeptin receptor coupling to Gq/11 leads to phospholipase C activation and Ca2+ release, as well as activation of Rho and Rho-associated kinase. However, the specific mechanisms by which these activation are induced by kisspeptin-10 remain to be investigated. In our study, these pathways were detected by gene chip and analyzed with KEGG pathway analysis. The results identified several pathways involved in heart diseases. The two differentially expressed genes ITGA4 and ITGB8 are present in heart disease-related pathways, including Dilated Cardiomyopathy (DCM), Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), and hypertrophic cardiomyopathy (HCM). The expression of these two genes was upregulated at the transcriptional and protein levels after kisspeptin-10 treatment in our study.” (11)“Activation of native GPR54 by kisspeptin-10 initiated [Ca2+]i oscillations in quiescent GnRH-1 cells, increased the frequency of calcium spiking in oscillating cells that led to summation of individual spikes into plateau-bursting type of calcium signals in a subset of active cells. These changes predominantly reflected the stimulatory effect of GPR54 activation on the plasma membrane oscillator activity via coupling of this receptor to phospholipase C signaling pathways. Both components of this pathway, inositol 1,3,4-trisphosphate and protein kinase C, contributed to the receptor-mediated modulation of baseline [Ca2+]i oscillations.” (12)
“...kisspeptin increased free intracellular Ca2+ values ([Ca2+]i) through protein kinase C (PKC) activation in GT1-7 cells… Kisspeptin-10 caused [Ca2+]i transients in hippocampal neurons. The change in [Ca2+]i by 100 nM kisspeptin was prevented by pre-treating the cells in PKC inhibitor chelerythrine chloride. According to the results, kisspeptin activates intracellular calcium signaling in hippocampal neurons via the pathway that depends on PKC. The results of this study suggest that kisspeptin may have a role in hippocampal neuron functions.” (13)
https://www.nature.com/articles/s41598-018-20571-2