GLP-1 Increases Preovulatory LH Source and the Number of Mature Follicles, As Well As Synchronizing the Onset of Puberty in Female Rats

Abstract

Control of estrous cycle and reproductive capacity involves a large number of central and peripheral factors, integrating numerous nutritional and metabolic signals. Here we show that glucagon-like peptide-1 (GLP-1), a peptide with anorexigenic and insulinotropic actions, and the GLP-1 receptor agonist Exendin-4 (Ex4) exert a regulatory influence on the gonadal axis, in both adult and prepubertal female rats. In adult rats, Glp-1 receptor expression varies during the estrous cycle at the hypothalamus, pituitary, and ovary. Furthermore, acute treatment with GLP-1 in the morning proestrus doubled the amplitude of the preovulatory LH surge, as well as influencing estradiol and progesterone levels along the estrous cycle. These changes provoked an important increase in the number of Graafian follicles and corpora lutea, as well as in the litter size. Conversely, Ex4 diminished the levels of LH, later producing a partial blockade at the preovulatory surge, yet not affecting either the number of mature follicles or corpora lutea. Chronic administration of low doses of GLP-1 to prepubertal rats synchronized vaginal opening and increased LH levels on the 35th day of life, yet at these doses it did not modify their body weight, food intake, or ovarian and uterine weight. By contrast, chronic exposure to Ex4 produced a significant reduction in ovarian and uterine weight, and serum LH, and the animals treated chronically with Ex4 showed no vaginal opening in the period studied. Overall, our results demonstrate that GLP-1 and Ex4 act on the gonadal axis, involving the hypothalamic kisspeptin system, to influence reproductive efficiency in female rats.

Glucagon-Like Peptide-1 Excites Firing and Increases GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and Suppression of Endocannabinoid Signaling Pathways

“…The intracellularly applied NO-scavenger CPTIO, the TRPV1 inhibitor AMG9810 and the FAAH inhibitor PF3845 were effective, too, confirming further the direct action of Exendin-4 in GnRH neurons. Thus, direct effect of GLP-1 agonist on GnRH neurons is revealed beside its earlier suggested indirect action via kisspeptin neurons (Outeiriño-Iglesias et al, 2015). …”

“…Our data are in accordance with a recent investigation showing stimulatory effect of GLP-1 in neurons of the paraventricular nucleus, the bed nucleus of the stria terminalis and the hippocampus (Cork et al, 2015). Excitatory role of GLP-1 on the reproductive axis has already been suggested, too (Beak et al, 1998; MacLusky et al, 2000; Outeiriño-Iglesias et al, 2015). Our finding is also supported by other studies showing increased spike and mPSC frequency in hypothalamic hypocretin/orexin neurons (Acuna-Goycolea and van den Pol, 2004) or revealing elevated c-fos level and firing rate in neurons of parabrachial nucleus (Richard et al, 2014).…”

“…Male GLP-1R knockout mice exhibited reduced gonadal weights, and females possessed a slight delay in the onset of puberty (MacLusky et al, 2000). GLP-1 doubled the amplitude of the preovulatory LH surge, influenced estradiol and progesterone levels and increased the number of Graafian follicles and corpora lutea (Outeiriño-Iglesias et al, 2015). Since GnRH neurons orchestrate the hypothalamo-pituitary-gonadal axis, any GLP-1-induced modulation of the GnRH neuronal system itself has a major impact on various events of reproductive physiology.…”

GLP-1R Signaling Directly Activates Arcuate Nucleus Kisspeptin Action in Brain Slices but Does not Rescue Luteinizing Hormone Inhibition in Ovariectomized Mice During Negative Energy Balance

“…Functional studies indicate that GLP-1 promotes GnRH secretion from isolated hypothalamic tissue and acts centrally to enhance LH levels in male rats (Beak et al, 1998). More recent studies demonstrate that GLP-1 acts centrally to enhance the preovulatory LH surge of intact female rats (Outeirino-Iglesias et al, 2015). Taken together, these data suggest that GLP-1 promotes GnRH/LH release.…”

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“…However, studies in humans with short-term infusions of GLP1Ra showed only transient increases in circulating levels of ACTH and cortisol [148] . Recent studies demonstrated the effects of exendin-4 on the hypothalamic-pituitary-adrenal axis with secretion of corticosteroids in male mice [149] and in the reproduction of female mice by increases in LH and the number of mature follicles [150]. Despite the presence of GLP-1R in culture of parafollicular C-cell tumors, the use of GLP1Ra was not associated with the diagnosis of medullary thyroid carcinoma in humans [83,151] Since the beginning of incretin-based therapy in T2DM patients, questions remain about the use of this therapy in T1D patients [152] .…”