Human sperm express the receptor for glucagon-like peptide-1 (GLP-1) which affects sperm function and metabolism.

AIM: Glucagon-like peptide-1 (GLP1) produces pleiotropic effects binding to the GLP1 receptor (GLP1-R) potentiating insulin secretion in the pancreas. GLP1-R is expressed in peripheral tissues and evidence for its role in reproduction came from knockout mice, although the relationship between GLP1 and male fertility needs to be clarified. Given that human sperm is an insulin-sensitive and insulin-secreting cell, we hypothesized that GLP-1/GLP1-R axis may be expressed and functional in these cells. RESULTS: and discussion: We evidenced GLP1-R presence by Western blotting and immunofluorescence analyses. Since Exendin-4 (Ex-4) displays similar functional properties to native GLP-1 we used this agonist to perform a dose-response study on progressive motility and cholesterol efflux, showing that 300 pM Ex-4 was the most effective treatment. These actions are mediated by GLP1-R and independent from sperm-secreted insulin. The exposure to Ex-4 fueled the PI3K/AKT signaling and reversed by H89, indicating a PKA-dependence of GLP1/GLP1-R signaling. It emerged that in sperm, insulin secretion regulated by Ex-4 did not occur in a strictly glucose-dependent manner. A stimulatory action of Ex-4/GLP1-R on LDH and G6PDH activities was observed. The Ex-4/GLP1-R decreased triglycerides content concomitantly to an enhanced lipase and Acyl-CoA dehydrogenase activities, addressing a lipolytic effect. CONCLUSION: Collectively, we discovered that human sperm is a new GLP1 incretin target broadening our knowledge about the effects of the GLP1-R agonist in male reproductive field. Further findings in humans should be conducted in the future to confirm it and to improve the translational aspect of this study.