title: Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility?
abstract: Human feeding behavior and lifestyle are gradually being altered, favoring the development of metabolic diseases, particularly type 2 diabetes and obesity. Leptin is produced by the adipose tissue acting as a satiety signal. Its levels have been positively correlated with fat mass and hyperleptinemia has been proposed to negatively affect male reproductive function. Nevertheless, the molecular mechanisms by which this hormone affects male fertility remain unknown. Herein, we hypothesize that leptin acts on human Sertoli cells (hSCs), the "nurse cells" of spermatogenesis, altering their metabolism. To test our hypothesis, hSCs were cultured without or with leptin (5, 25 and 50ng/mL). Leptin receptor was identified by qPCR and Western blot. Protein levels of glucose transporters (GLUT1, GLUT2 and GLUT3), phosphofructokinase, lactate dehydrogenase (LDH) and monocarboxylate transporter 4 (MCT4) were determined by Western Blot. LDH activity was assessed and metabolite production/consumption determined by proton nuclear magnetic resonance. Oxidative damage was evaluated by assessing lipid peroxidation, protein carbonilation and nitration. Our data shows that leptin receptor is expressed in hSCs. The concentration of leptin found in lean, healthy patients, upregulated GLUT2 protein levels and concentrations of leptin found in lean and obese patients increased LDH activity. Of note, all leptin concentrations decreased hSCs acetate production illustrating a novel mechanism for this hormone action. Moreover, our data shows that leptin does not induce or protect hSCs from oxidative damage. We report that this hormone modulates the nutritional support of spermatogenesis, illustrating a novel mechanism that may be linked to obesity-induced male infertility.
authors.affiliation: Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Covilhã, Portugal; Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar (UMIB-ICBAS), University of Porto, Porto, Portugal.
authors.forename: Ana D
authors.initials: AD
authors.lastname: Martins
authors.affiliation: Institute for Molecular and Cell Biology (IBMC), University of Porto, Portugal.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Moreira
authors.affiliation: Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar (UMIB-ICBAS), University of Porto, Porto, Portugal.
authors.forename: Rosália
authors.initials: R
authors.lastname: Sá
authors.affiliation: Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar (UMIB-ICBAS), University of Porto, Porto, Portugal; Department of Anatomy, Institute of Biomedical Sciences Abel Salazar (ICBAS) University of Porto, Porto, Portugal.
authors.forename: Mariana P
authors.initials: MP
authors.lastname: Monteiro
authors.affiliation: Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar (UMIB-ICBAS), University of Porto, Porto, Portugal; Centre for Reproductive Genetics Prof. Alberto Barros, Porto, Portugal.
authors.forename: Mário
authors.initials: M
authors.lastname: Sousa
authors.affiliation: Department of Life Sciences, Faculty of Sciences and Technology and Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal.
authors.forename: Rui A
authors.initials: RA
authors.lastname: Carvalho
authors.affiliation: Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Covilhã, Portugal.
authors.forename: Branca M
authors.initials: BM
authors.lastname: Silva
authors.affiliation: Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Covilhã, Portugal; Department of Microscopy, Laboratory of Cell Biology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar (UMIB-ICBAS), University of Porto, Porto, Portugal.
authors.forename: Pedro F
authors.initials: PF
authors.lastname: Oliveira
authors.affiliation: Health Sciences Research Centre (CICS-UBI), University of Beira Interior, Covilhã, Portugal; Department of Life Sciences, Faculty of Sciences and Technology and Center for Neurosciences and Cell Biology (CNC), University of Coimbra, Coimbra, Portugal. Electronic address: alvesmarc@gmail.com.
authors.forename: Marco G
authors.initials: MG
authors.lastname: Alves
keywords: Leptin; Male fertility; Obesity; Sertoli cells; Spermatogenesis