A Pharmacological Dose of Liraglutide Improves Mitochondrial Performance in Mouse Leydig Cells

Male fertility has declined over the years, partly due to metabolic disorders such as obesity and Type 2 diabetes. Antidiabetic drugs, including GLP-1 receptor agonists like liraglutide, are widely used to manage these conditions and aid in weight loss. Within the male reproductive tract, Leydig cells (LCs) are essential since they produce testosterone. Notably, the influence of antidiabetics on LCs remains a subject of limited investigation. Herein, we aimed to evaluate the effect of liraglutide on the physiology of LCs. To this end, we cultured LCs (BLTK1 cell line) without (control) or in the presence of selected concentrations of liraglutide. We then assessed their metabolic viability, cell proliferation, LDH release, ROS production, mitochondrial membrane potential, and in vivo mitochondrial cell performance, as well as the number of mtDNA copies. We also measured androstenedione production. Our results showed that liraglutide at pharmacological and supra-pharmacological concentrations increased the metabolic viability of LCs and reduced ROS production at all concentrations. Furthermore, the pharmacological concentration of liraglutide increased the basal respiration, maximal respiration, proton leak, and oxygen consumption rate related to ATP-linked production. Androstenedione production remained unchanged, which may be related to the inherent limitations of the cell line in supporting steroidogenesis. Overall, our findings suggest that liraglutide exhibits a potential protective effect on LC function, particularly by enhancing metabolic viability, reducing oxidative stress, and improving mitochondrial performance, highlighting its potential beyond the established role in diabetes and weight management.