Pioglitazone increases the glycolytic efficiency of human Sertoli cells with possible implications for spermatogenesis |
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| Institution: | 1. University of Beira Interior, Rua Marquês d''Ávila e Bolama, 6201-001 Covilhã, Portugal;2. Department of Microscopy, Laboratory of Cell Biology, Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Rua Jorge Viterbo Ferreira, 4050-313 Porto, Portugal;3. Department of Life Sciences, Faculty of Sciences and Technology and Centre for Functional Ecology (CFE), University of Coimbra, Coimbra, Portugal;4. i3S – Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen, 4200-135 Porto, Portugal;5. Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa;6. Human Metabolomics, North-West University, Private Bag X6001, Box 269, Potchefstroom 2520, South Africa;1. INSERM UMR 1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France;2. INSERM UMR 1124, Centre Universitaire des Saints-Pères, Université Paris Descartes, Sorbonne Paris Cité, Paris, France;3. Reference Center for Inherited Metabolic Diseases, Hôpital Robert Debré, Assistance Publique – Hôpitaux de Paris, 48 Boulevard Sérurier, 75019 Paris, France;4. Equipe11 labellisée Ligue Nationale contre le Cancer, Centre de Recherche des Cordeliers, Paris, France;5. INSERM U1138, Centre de Recherche des Cordeliers, Paris, France;6. Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France;7. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France;8. Karolinska Institute, Department of Women''s and Children''s Health, Karolinska University Hospital, Stockholm 17176, Sweden;9. MRC-Mitochondrial Biology Unit, Cambridge, Cambridgeshire, United Kingdom |
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| Abstract: | Pioglitazone is a synthetic agonist for the nuclear receptor peroxisome proliferator-activated receptor γ used to treat type 2 diabetes mellitus. Recently we reported that antidiabetic drugs regulate the nutritional support of spermatogenesis by Sertoli cells. Herein, we investigate the effects of pioglitazone on human Sertoli cells metabolism. Human Sertoli cells were cultured in the presence of pioglitazone (1, 10, 100 μM). Protein levels of phosphofructokinase 1, lactate dehydrogenase, hexokinase, glucose transporters (GLUT1, GLUT2, GLUT3), monocarboxylate transporter 4 and oxidative phosphorylation complexes were determined by Western blot. Lactate dehydrogenase and alanine aminotransferase activity were assessed and metabolite production and consumption determined by proton nuclear magnetic resonance. Mitochondrial membrane potential was also determined. Glucose consumption more than doubled in human Sertoli cells stimulated with pioglitazone 100 μM. Mitochondrial complex II protein levels increased 50% with exposure to pioglitazone (100 μM) in human Sertoli cells, though mitochondrial membrane potential was decreased by 32%. The pharmacological concentration of pioglitazone (10 μM) almost doubled lactate production and established crucial correlations among key intervenient of glycolysis. Moreover, in the same concentration, alanine aminotransferase decreased more than 80%. Our results suggest that pioglitazone (10 μM) increases the efficiency of the glycolytic flux and lactate production by human Sertoli cells, which is essential to sustain and preserve the spermatogenic event. Thus, pioglitazone may improve male fertility and thus, be considered a suitable antidiabetic drug for men in reproductive age. |
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| Keywords: | Pioglitazone Spermatogenesis Sertoli cells Mitochondria |
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