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

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.