Glucagon-like peptide-1 control of GnRH secretion in female sheep

Abstract

The role of glucagon-like peptide-1 (GLP-1) on gonadotropin releasing hormone (GnRH) secretion was investigated in ovariectomised (OVX) ewes, in which GnRH and luteinising hormone (LH) secretion had been restrained by treatment with estrogen and progesterone. Guide tubes for microinjection were placed above the ME and the animals allowed to recover for 1 month. Jugular venous blood samples were taken via cannulae at 10 min intervals. Vehicle (50nl) was injected into the ME at 2h, followed by injection of GLP-1 ((7-36)-amide - 0.5 or 1 nmole) or its receptor agonist, exendin 4 (0.5 nmole) at 4h (n=5). Plasma LH levels were quantified as a surrogate measure of GnRH secretion. GLP-1 microinjection into the ME elicited a large amplitude LH pulse in jugular plasma, the effect was greater at the higher dose. Exendin-4 microinjection caused a large, sustained increase in plasma LH levels. To determine how GLP-1 might exert an effect on GnRH secretion, we employed double labelled in situ hybridisation, with RNAScope, for co-localisation of the GLP-1 receptor (GLP-1R) in GnRH, Kisspeptin and NPY cells in the hypothalami of 3 ewes in the luteal phase of the estrous cycle. GLP-1R expression was clearly visible but the receptor was not expressed in GNRH1 or NPY expressing neurons and was visualised in <5% of KISS1 expressing neurons. We conclude that GLP-1 may act at the level of the secretory terminals of GnRH neurons in the ME to stimulate GnRH secretion, the pathway through which such effect is manifest remains unknown.

The GLP-1 agonist, exendin-4, stimulates LH secretion in female sheep

“…This is supported by our earlier work, which indicated that direct injection into the ME enhanced LH pulse amplitude. This suggests an effect on the release of GnRH at the level of the GnRH neuronal dendrites in the external zone of the ME ( Arbabi et al 2021 ).…”

“…Both exendin-4 and GLP-1 are able to penetrate the blood−brain barrier ( Kastin & Akerstrom 2003 ) enabling action on kisspeptin and/or GnRH-producing neurons to alter downstream LH secretion. Gut-derived GLP-1 or systemically administered exendin-4 could also act outside the blood–brain barrier at the level of the ME ( Arbabi et al 2021 ) or pituitary gland ( Khan et al 2022 ). The rapid LH response seen to exendin-4 infusion in the present study tends to support the notion that GLP-1 influences GnRH secretion without entering the brain.…”

“…One ewe appeared to respond during the period the infusion lines were being primed; perhaps due to inadvertent administration of the drug. The ME, which contains GnRH neurons, has a dense population of GLP-1 receptors ( Larsen et al 1997 ) and the increase in LH seen after micro-injection of GLP-1/exendin-4 into the ME suggests that circulating GLP-1 most likely acts on the neurosecretory terminals of GnRH neurons in this area ( Arbabi et al 2021 ). On the other hand, GLP-1 binding to rat pituitary is reported ( Shimuzu et al 1987 ), as is GLP-1R RNA expression ( Outeirino-Iglesias et al 2015 , Khan et al 2022 ) and action at this level cannot be excluded.…”

“…It has been reported that microinjection of either GLP-1 or exendin-4 into the ME stimulated LH secretion in OVX ewes, strongly suggesting action at the level of GnRH terminals ( Arbabi et al 2021 ). Given that the ME is outside the blood–brain barrier, it is possible that circulating GLP-1 can stimulate the gonadotrophic axis through action at this level.…”

Metabolic hormones are integral regulators of female reproductive health and function

“…Changes in gonadotropin secretion appear to be due in part to GLP-1 positively regulating GnRH release. Early evidence in a rat hypothalamic cell-line pointed to GLP-1 promoting GnRH release via intracellular cAMP signaling [ 315 ], and subsequent work implicated the involvement of Kiss1 neurons [ 314 , 316 , 317 ] and GABAergic signals [ 318 ] in bolstering the direct effects of GLP-1 on GnRH neurons. While there is less known about the role of GIP, GIPR is expressed in the murine hypothalamus [ 319 ] and pituitary [ 311 ], and intracerebroventricular GIP administration decreases plasma FSH levels in rats [ 320 ].…”