Kisspeptin Stimulates Growth Hormone Release by Utilizing Neuropeptide Y Pathways and Is Dependent on the Presence of Ghrelin in the Ewe

Foradori, Chad D.; Whitlock, Brian K; Daniel, Joseph A; Zimmerman, Arthur D.; Jones, Marshall; Read, Casey C; Steele, Barbara P; Smith, Jeremy Troy; Clarke, I. J.; Elsasser, Theodore H.; Keisler, D.H.; Sartin, James L.

doi:10.1210/en.2017-00303

Cited by 20 publications

(22 citation statements)

References 88 publications

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“…We attempted to clarify the field by utilising specific antagonists to GPR54. In our study, we found no effect of administration of kisspeptin into the LV on GH secretion in intact ewes, which is in agreement with the reported lack of response to peripheral administration in intact cows studies (Whitlock et al 2008) and prepubertal female pigs (Lents et al 2008) but contrasts with a small GH increase reported in ewes (Whitlock et al 2010) although the immediate nutritional status may be key in this model (Foradori et al 2017). In women, both acute and chronic peripheral administration of kisspeptin-54 failed to alter GH concentrations (Jayasena et al 2014).…”

Section: Discussionsupporting

confidence: 91%

“…However, recently published data show kisspeptin can stimulate GH, but only in fasted ewes, by a ghrelin-NPYmediated mechanism (Foradori et al 2017). These complex, and often, contradictory reports may be a result of the large family of RFamide receptors, which can be targeted by kisspeptin.…”

Section: Discussionmentioning

confidence: 99%

“…Kisspeptin neuron activity is essential for the stimulation of GnRH secretion (Gottsch et al 2004, Han et al 2005) and mediates both negative and positive feedback regulation by gonadal function (Hull & Harvey 2001, 2002 and in metabolic regulation. A substantial number of studies have now reported effects of kisspeptin on GH secretion in various species, under different physiological conditions, using peripheral or central administration, and by examining direct effects on pituitary cells in culture (Gutierrez-Pascual et al 2007, Kadokawa et al 2007, Lents et al 2008, Whitlock et al 2008, Foradori et al 2017. Kisspeptin is a member of the large family of RFamide peptides that target an equally large family of cognate receptors (Dockray 2004).…”

Section: Introductionmentioning

confidence: 99%

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Stimulation of growth hormone by kisspeptin antagonists in ewes

Smith

Roseweir

Millar

et al. 2018

Journal of Endocrinology

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Kisspeptin signalling is indispensable for fertility, stimulating gonadotropin-releasing hormone (GnRH) secretion and mediating gonadal steroid feedback on GnRH neurons. Moreover, kisspeptin neurons have been implicated in other non-reproductive neuroendocrine roles. Kisspeptin appears to also regulate growth hormone secretion but much of the data appear contradictory. We sought to clarify a potential role of kisspeptin in growth hormone (GH) regulation by examining the effect of kisspeptin antagonists on GH secretion in ewes under various physiological conditions. Our data show clear and robust increases in GH secretion following lateral ventricle or third ventricle infusion of kisspeptin antagonists p-234 and p-271 in either ovariectomized or anestrous ewes. Central infusion of kisspeptin-10 had no effect on GH secretion. To determine the level at which kisspeptin may influence GH secretion, we examined expression of the cognate kisspeptin receptor, GPR54, in pituitary cells and showed by immunocytochemistry that the majority of somatotropes express GPR54 while expression was largely negative in other pituitary cells. Overall, we have demonstrated that blocking kisspeptin signalling by antagonists stimulates GH secretion in ewes and that this is likely mediated by inhibiting endogenous kisspeptin activation of GPR54 expressed on somatotropes. The findings suggest that endogenous kisspeptin inhibits GH secretion through GPR54 expressed on somatotropes.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Stimulation of growth hormone by kisspeptin antagonists in ewes

Smith

Roseweir

Millar

et al. 2018

Journal of Endocrinology

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“…The molecular and cellular regulation of folliculogenesis is complex and not fully understood. NPY is known to regulate female reproductive function through the central neuron system [6]; NPY at the hypothalamus modulates the activity of GnRH neuronal system via NPY1R and NPY2R and regulates LH secretion by the pituitary gland [15][16][17][18][19][20][21]. However, its role in the control of the follicular development at the ovarian level has not been reported.…”

Section: Discussionmentioning

confidence: 99%

Neuropeptide Y regulates proliferation and apoptosis in granulosa cells in a follicular stage-dependent manner

et al. 2020

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Background: The complex regulatory mechanism involved in ovarian follicular development is not completely understood. Neuronal neuropeptide Y (NPY) is involved in the regulation of feeding behavior, energy homeostasis, and reproduction behavior, while its function in ovarian follicular development is not clear. The objective of this study was to investigate if and how NPY regulates follicle development in the ovary. Methods: All experiments were performed using Sprague Dawley rats. To understand NPY expression pattern at different stages of follicular development, NPY content was assessed using immunohistochemistry in individual follicles. NPY and its receptors expression pattern were evaluated in granulosa cells isolated from preantral (PA), early antral (EA) and late antral follicles (LAF). The influence of NPY on granulosa cell proliferation and apoptosis were further assessed in vitro, using Ki67-and TUNEL-positivity assays. To investigate whether NPY induced-proliferation in EA granulosa cells is mediated through the activation of NPY receptor Y5 (NPY5R) and Mitogen-activated protein kinase (MEK) signal pathway, EA granulosa cells were treated with NPY5R antagonist (CGP71683) and MEK inhibitors (PD98059 and U0126), and Ki67-positive cells were assessed. Results: NPY protein expression was follicular stage-dependent and cell type-specific. NPY signal intensity in EA was higher than those in PA and LAF. Antral granulosa cells showed the highest signal intensity compared to mural granulosa cells, cumulus cells and theca cells. Granulosa cells NPY protein content and mRNA abundance were higher in EA than in LAF. NPY receptor contents in granulosa cells were follicular stage-dependent. While NPY reduced apoptosis of EA granulosa cells, it increased the proliferation through NPY5R and MEK pathway. In contrast, in LAF granulosa cells, NPY reduced proliferation and increased the number of apoptotic cells, with no significant effects on PA granulosa cells. Conclusion: This study is the first to evaluate the intraovarian role of NPY in granulosa cells at various stage of follicular development. These results indicate that NPY regulates granulosa cells proliferation and apoptosis in a follicular stage-dependent and autocrine manner. NPY may play a role in pathogenesis of ovarian follicular disorders.

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“…In mammals, the reproductive axis also is regulated by energy balance ( 35 ) and kisspeptin is related to food intake and growth ( 55 , 56 ). Although several recent studies have proposed that kisspeptins regulate reproduction in teleosts, little is known about their role in the control of food intake and energy balance.…”

Section: Discussionmentioning

confidence: 99%

Evidence of Alternative Splicing as a Regulatory Mechanism for Kissr2 in Pejerrey Fish

et al. 2018

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Kisspeptin receptors are G-Protein-Coupled Receptors that regulate GnRH synthesis and release in vertebrates. Here, we report the gene structure of two kisspeptin receptors (kissr2 and kissr3) in pejerrey fish. Genomic analysis exposed a gene structure with 5 exons and 4 introns for kissr2 and 6 exons and 5 introns for kissr3. Two alternative variants for both genes, named kissr2_v1 and _v2, and kissr3_v1 and v2, were revealed by gene expression analyses of several tissues. For both receptors, these variants were originated by alternative splicing retaining intron 3 and intron 4 for kissr2_v2 and kissr3_v2, respectively. In the case of kissr2, the intron retention introduced two stop codons leading to a putatively truncated protein whereas for kissr3, the intron retention produced a reading shift leading to a stop codon in exon 5. Modeling and structural analysis of Kissr2 and Kissr3 spliced variants revealed that truncation of the proteins may lead to non-functional proteins, as the structural elements missing are critical for receptor function. To understand the functional significance of splicing variants, the expression pattern for kissr2 was characterized on fish subjected to different diets. Fasting induced an up-regulation of kissr2_v1 in the hypothalamus, a brain region implicated in control of reproduction and food intake, with no expression of kissr2_v2. On the other hand, fasting did not elicit differential expression in testes and habenula. These results suggest that alternative splicing may play a role in regulating Kissr2 function in pejerrey.

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Kisspeptin Stimulates Growth Hormone Release by Utilizing Neuropeptide Y Pathways and Is Dependent on the Presence of Ghrelin in the Ewe

Cited by 20 publications

References 88 publications

Stimulation of growth hormone by kisspeptin antagonists in ewes

Stimulation of growth hormone by kisspeptin antagonists in ewes

Neuropeptide Y regulates proliferation and apoptosis in granulosa cells in a follicular stage-dependent manner

Evidence of Alternative Splicing as a Regulatory Mechanism for Kissr2 in Pejerrey Fish

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