GLP-1 is secreted from the distal ileum/colon in response to feeding and regulates insulin secretion and glucose levels. GLP- also acts on neurons within the hypothalamus (1). GLP-1 treatment increased luteinizing hormone (LH) blood levels in rats, but the GLP-1 agonist Exendin-4 had the opposite effect (2). Whether GLP-1 affects the reproductive axis is important because of licenced weight-loss therapeutics such as Liraglutide (GLP-1 agonist) (3). We aimed to determine the effects of GLP-1 and Exendin-4 on GnRH secretion in sheep. Ovariectomised ewes (n=5/group), treated with estradiol and progesterone to suppress GnRH/LH secretion, received implanted guide tubes directed 2mm above the median eminence (ME). We have shown previously (4) that GnRH secretion is controlled at this level by kisspeptin. Jugular blood samples were taken each 10 min for 2h. Then, 50 nanolitres 0.9% saline vehicle was injected into the ME. After a further 2h sampling, 0.5 nmole of either human GLP-1 or Exendin-4 was injected and samples were taken for 2h. As compared to the vehicle injection, mean plasma LH levels (in ng/ml ±SEM), reflecting GnRH secretion, were increased by GLP-1 (from 0.5±0.11 to 0.8±0.17; P<0.05) and Exendin-4 (from 0.9±0.22 to 2.3±0.12; P<0.005). Exendin-4 induced a more sustained elevation in LH secretion than GLP-1. Preliminary in situ hybridization for the GLP-1 receptor showed labelling of cells in the preoptic area and arcuate nucleus of the ovine brain and determination of the cells that express this receptor is pending. We conclude that GnRH secretion is increased by GLP-1 and its receptor agonist, Exendin-4. This has implications for therapeutics which target GLP-1 receptors for weight control.
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