GnRH(1-5), a metabolite of gonadotropin-releasing hormone, enhances luteinizing hormone release via activation of kisspeptin neurons in female rats

Jan 17, 2020Endocrine journal

A breakdown product of reproductive hormone may increase luteinizing hormone by activating hormone-controlling neurons in female rats

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Abstract

Intracerebroventricular injection of GnRH(1-5) at 2 nmol significantly increased plasma LH concentration in ovariectomized and estrogen-treated female rats.

GnRH(1-5) administration led to higher levels of plasma LH compared to controls.
The increase in LH secretion was not observed in Kiss1 knockout rats, indicating kisspeptin neurons mediate this effect.
Double in situ hybridization showed limited coexpression of Kiss1 and the GnRH(1-5) receptor gene Gpr101 in both ARC and AVPV regions.
Approximately 29.2% of Gpr101-expressing cells in the ARC also coexpressed a glutamatergic marker, suggesting a potential interaction.
Most Kiss1-expressing cells in the AVPV and ARC coexpressed a gene related to NMDA receptors, indicating a role for glutamatergic signaling.

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Accumulating evidence suggests that kisspeptin neurons in the arcuate nucleus (ARC), which coexpress neurokinin B and dynorphin, are involved in gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) pulse generation, while the anteroventral periventricular nucleus (AVPV) kisspeptin neurons are responsible for GnRH/LH surge generation. The present study aims to examine whether GnRH(1-5), a GnRH metabolite, regulates LH release via kisspeptin neurons. GnRH(1-5) was intracerebroventricularly injected to ovariectomized and estrogen-treated Wistar-Imamichi female rats. Immediately after the central GnRH(1-5) administration at 2 nmol, plasma LH concentration increased, resulting in significantly higher levels of the area under the curve and baseline of plasma LH concentrations compared to vehicle-injected controls. On the other hand, in Kiss1 knockout rats, GnRH(1-5) administration failed to affect LH secretion, suggesting that the facilitatory effect of GnRH(1-5) on LH release is mediated by kisspeptin neurons. Double in situ hybridization (ISH) for Kiss1 and Gpr101, a GnRH(1-5) receptor gene, revealed that few Kiss1-expressing cells coexpress Gpr101 in both ARC and AVPV. On the other hand, double ISH for Gpr101 and Slc17a6, a glutamatergic marker gene, revealed that 29.2% of ARC Gpr101-expressing cells coexpress Slc17a6. Further, most of the AVPV and ARC Kiss1-expressing cells coexpress Grin1, a gene encoding a subunit of NMDA receptor. Taken together, these results suggest that the GnRH(1-5)-GPR101 signaling facilitates LH release via indirect activation of kisspeptin neurons and that glutamatergic neurons may mediate the signaling. This provides a new aspect of kisspeptin- and GnRH-neuronal communication with the presence of stimulation from GnRH to kisspeptin neurons in female rats.

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GnRH(1-5), a metabolite of gonadotropin-releasing hormone, enhances luteinizing hormone release via activation of kisspeptin neurons in female rats

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