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Sertoli Cells pp 129-155 | Cite as

Molecular Mechanisms and Signaling Pathways Involved in the Nutritional Support of Spermatogenesis by Sertoli Cells

  • Luís Crisóstomo
  • Marco G. Alves
  • Agostina Gorga
  • Mário Sousa
  • María F. Riera
  • María N. Galardo
  • Silvina B. MeroniEmail author
  • Pedro F. Oliveira
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1748)

Abstract

Sertoli cells play a central role in spermatogenesis. They maintain the blood-testis barrier, an essential feature of seminiferous tubules which creates the proper environment for the occurrence of the spermatogenesis. However, this confinement renders germ cells almost exclusively dependent on Sertoli cells’ nursing function and support. Throughout spermatogenesis, differentiating sperm cells become more specialized, and their biochemical machinery is insufficient to meet their metabolic demands. Although the needs are not the same at all differentiation stages, Sertoli cells are able to satisfy their needs. In order to maintain the seminiferous tubule energetic homeostasis, Sertoli cells react in response to several metabolic stimuli, through signaling cascades. The AMP-activated kinase, sensitive to the global energetic status; the hypoxia-inducible factors, sensitive to oxygen concentration; and the peroxisome proliferator-activated receptors, sensitive to fatty acid availability, are pathways already described in Sertoli cells. These cells’ metabolism also reflects the whole-body metabolic dynamics. Metabolic diseases, including obesity and type II diabetes mellitus, induce changes that, both directly and indirectly, affect Sertoli cell function and, ultimately, (dys)function in male reproductive health. Insulin resistance, increased estrogen synthesis, vascular disease, and pubic fat accumulation are examples of metabolic-related conditions that affect male fertility potential. On the other hand, malnutrition can also induce negative effects on male sexual function. In this chapter, we review the molecular mechanisms associated with the nutritional state and male sexual (dys)function and the central role played by the Sertoli cells.

Keywords

Nutritional support AMPK PPAR HIF Metabolic (dys)function 

Notes

Acknowledgments

This work was supported by the “Fundação para a Ciência e a Tecnologia” (FCT) and co-funded by Fundo Europeu de Desenvolvimento Regional (FEDER) via Programa Operacional Factores de Competitividade COMPETE/QREN to UMIB (Pest OE/SAU/UI0215/2014); POCI—COMPETE 2020—Operational Programme Competitiveness and Internationalization in Axis I (Strengthening research, technological development and innovation) (Project No. 007491); and National Funds of FCT (Foundation for Science and Technology): PF Oliveira (PTDC/BBB-BQB/1368/2014 and IFCT2015) and MG Alves (PTDC/BIM-MET/4712/2014 and IFCT2015). L Crisóstomo was funded by the fellowship “Bolsa Nuno Castel-Branco” from the Portuguese Society of Diabetology. This work was also supported by grants from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCYT) (PICT 2014/945) and the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) (PIP 2015/1827). M.F. Riera, M.N. Galardo, and S.B. Meroni are established investigators of CONICET. A. Gorga is a recipient of ANPCYT fellowship.

References

  1. 1.
    Rato L, Alves MG, Socorro S, Duarte AI, Cavaco JE, Oliveira PF (2012) Metabolic regulation is important for spermatogenesis. Nat Rev Urol 9(6):330–338. https://doi.org/10.1038/nrurol.2012.77 PubMedCrossRefGoogle Scholar
  2. 2.
    Griswold MD (1998) The central role of Sertoli cells in spermatogenesis. Semin Cell Dev Biol 9:411–416PubMedCrossRefGoogle Scholar
  3. 3.
    Sertoli E (1865) Dell’esistenza di particolari cellule ramificate nei canalicoli seminiferi del testicolo umano. Il Morgagni 7:31–39Google Scholar
  4. 4.
    von Ebner V (1887) Zur spermatogenese bei den säugethieren. Arch Mikrosk Anat 31(1):236–292CrossRefGoogle Scholar
  5. 5.
    França L, Hess R, Dufour J, Hofmann M, Griswold M (2016) The Sertoli cell: one hundred fifty years of beauty and plasticity. Andrology 4(2):182–212CrossRefGoogle Scholar
  6. 6.
    Oliveira PF, Alves MG (2015) Sertoli cell metabolism and spermatogenesis, Springer briefs in cell biology, 1st edn. Springer International Publishing, New York. https://doi.org/10.1007/978-3-319-19791-3 CrossRefGoogle Scholar
  7. 7.
    Rebourcet D, O’Shaughnessy PJ, Monteiro A, Milne L, Cruickshanks L, Jeffrey N, Guillou F, Freeman TC, Mitchell RT, Smith LB (2014) Sertoli cells maintain Leydig cell number and peritubular myoid cell activity in the adult mouse testis. PLoS One 9(8):e105687PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Nagano M, Avarbock MR, Leonida EB, Brinster CJ, Brinster RL (1998) Culture of mouse spermatogonial stem cells. Tissue Cell 30(4):389–397PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Xie L, Lin L, Tang Q, Li W, Huang T, Huo X, Liu X, Jiang J, He G, Ma L (2015) Sertoli cell-mediated differentiation of male germ cell-like cells from human umbilical cord Wharton’s jelly-derived mesenchymal stem cells in an in vitro co-culture system. Eur J Med Res 20(1):9–19PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Zanganeh BM, Rastegar T, Roudkenar MH, Kashani IR, Amidi F, Abolhasani F, Barbarestani M (2013) Co-culture of spermatogonial stem cells with sertoli cells in the presence of testosterone and FSH improved differentiation via up-regulation of post meiotic genes. Acta Med Iran 51(1):1–11Google Scholar
  11. 11.
    Johnson L, Thompson DL, Varner DD (2008) Role of Sertoli cell number and function on regulation of spermatogenesis. Anim Reprod Sci 105(1):23–51PubMedCrossRefGoogle Scholar
  12. 12.
    Schlatt S, Ehmcke J (2014) Regulation of spermatogenesis: an evolutionary biologist’s perspective. Semin Cell Dev Biol 29:2–16PubMedCrossRefGoogle Scholar
  13. 13.
    Orth JM, Gunsalus GL, Lamperti AA (1988) Evidence from Sertoli cell-depleted rats indicates that spermatid number in adults depends on numbers of Sertoli cells produced during perinatal development. Endocrinology 122(3):787–794PubMedCrossRefGoogle Scholar
  14. 14.
    Orth JM, Higginbotham C, Salisbury R (1984) Hemicastration causes and testosterone prevents enhanced uptake of [3H] thymidine by Sertoli cells in testes of immature rats. Biol Reprod 30(1):263–270PubMedCrossRefGoogle Scholar
  15. 15.
    Simorangkir D, De Kretser D, Wreford N (1995) Increased numbers of Sertoli and germ cells in adult rat testes induced by synergistic action of transient neonatal hypothyroidism and neonatal hemicastration. J Reprod Fertil 104(2):207–213PubMedCrossRefGoogle Scholar
  16. 16.
    Layman LC, Porto AL, Xie J, Da Motta LACR, Da Motta LDC, Weiser W, Sluss PM (2002) FSHβ gene mutations in a female with partial breast development and a male sibling with normal puberty and azoospermia. J Clin Endocrinol Metab 87(8):3702–3707PubMedGoogle Scholar
  17. 17.
    Arslan M, Zaidi P, Akhtar FB, Amin S, Rana T, Qazi M (1981) Effects of gonadotrophin treatment in vivo on testicular function in immature rhesus monkeys (Macaca mulatta). Int J Androl 4(1–6):462–474PubMedCrossRefGoogle Scholar
  18. 18.
    Alves MG, Martins AD, Rato L, Moreira PI, Socorro S, Oliveira PF (2013) Molecular mechanisms beyond glucose transport in diabetes-related male infertility. Biochim Biophys Acta 1832(5):626–635. https://doi.org/10.1016/j.bbadis.2013.01.011 PubMedCrossRefGoogle Scholar
  19. 19.
    Dimitriadis F, Tsiampali C, Chaliasos N, Tsounapi P, Takenaka A, Sofikitis N (2015) The Sertoli cell as the orchestra conductor of spermatogenesis: spermatogenic cells dance to the tune of testosterone. Hormones 14(4):479–503PubMedGoogle Scholar
  20. 20.
    Oliveira PF, Martins AD, Moreira AC, Cheng CY, Alves MG (2015) The Warburg effect revisited—lesson from the Sertoli cell. Med Res Rev 35(1):126–151PubMedCrossRefGoogle Scholar
  21. 21.
    Rato L, Meneses MJ, Silva BM, Sousa M, Alves MG, Oliveira PF (2016) New insights on hormones and factors that modulate Sertoli cell metabolism. Histol Histopathol 31(5):499–513PubMedGoogle Scholar
  22. 22.
    Wong CH, Cheng CY (2005) The blood-testis barrier: its biology, regulation, and physiological role in spermatogenesis. In: Schatten GP (ed) Current topics in developmental biology, vol 71, 1st edn. Elsevier Inc., Amsterdam, pp 263–296. https://doi.org/10.1016/S0070-2153(05)71008-5 Google Scholar
  23. 23.
    Geens M, Sermon KD, Van de Velde H, Tournaye H (2011) Sertoli cell-conditioned medium induces germ cell differentiation in human embryonic stem cells. J Assist Reprod Genet 28(5):471–480PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Bernardino RL, Costa AR, Martins AD, Silva J, Barros A, Sousa M, Sá R, Alves MG, Oliveira PF (2016) Estradiol modulates Na+−dependent HCO3− transporters altering intracellular pH and ion transport in human Sertoli cells: a role on male fertility? Biol Cell 108(7):179–188PubMedCrossRefGoogle Scholar
  25. 25.
    Bernardino RL, Jesus TT, Martins AD, Sousa M, Barros A, Cavaco JE, Socorro S, Alves MG, Oliveira PF (2013) Molecular basis of bicarbonate membrane transport in the male reproductive tract. Curr Med Chem 20(32):4037–4049. https://doi.org/10.2174/15672050113109990200 PubMedCrossRefGoogle Scholar
  26. 26.
    Martins AD, Bernardino RL, Neuhaus-Oliveira A, Sousa M, Sá R, Alves MG, Oliveira PF (2014) Physiology of Na+/H+ exchangers in the male reproductive tract: relevance for male fertility. Biol Reprod 91(1):11–16PubMedCrossRefGoogle Scholar
  27. 27.
    Janecki A, Steinberger A (1986) Polarized Sertoli cell functions in a new two-compartment culture system. J Androl 7(1):69–71PubMedCrossRefGoogle Scholar
  28. 28.
    Vogl AW, Young J, Du M (2013) New insights into roles of tubulobulbar complexes in sperm release and turnover of blood-testis barrier. Int Rev Cell Mol Biol 303:319–355PubMedCrossRefGoogle Scholar
  29. 29.
    Cheng CY, Mruk DD (2002) Cell junction dynamics in the testis: Sertoli-germ cell interactions and male contraceptive development. Physiol Rev 82(4):825–874PubMedCrossRefGoogle Scholar
  30. 30.
    Alves MG, Rato L, Carvalho RA, Moreira PI, Socorro S, Oliveira PF (2013) Hormonal control of Sertoli cell metabolism regulates spermatogenesis. Cell Mol Life Sci 70(5):777–793. https://doi.org/10.1007/s00018-012-1079-1 PubMedCrossRefGoogle Scholar
  31. 31.
    Cardoso AM, Alves MG, Mathur PP, Oliveira PF, Cavaco JE, Rato L (2017) Obesogens and male fertility. Obes Rev 18(1):109–125PubMedCrossRefGoogle Scholar
  32. 32.
    Anderson JE, Thliveris JA (1986) Testicular histology in streptozotocin-induced diabetes. Anat Rec (Hoboken) 214(4):378–382. https://doi.org/10.1002/ar.1092140407 CrossRefGoogle Scholar
  33. 33.
    Whitmore LS, Ye P (2015) Dissecting germ cell metabolism through network modeling. PLoS One 10(9):e0137607PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Boussouar F, Benahmed M (2004) Lactate and energy metabolism in male germ cells. Trends Endocrinol Metab 15(7):345–350PubMedCrossRefGoogle Scholar
  35. 35.
    Miki K (2006) Energy metabolism and sperm function. Soc Reprod Fertil Suppl 65:309–325Google Scholar
  36. 36.
    Martins AD, Alves MG, Simões VL, Dias TR, Rato L, Moreira PI, Socorro S, Cavaco JE, Oliveira PF (2013) Control of Sertoli cell metabolism by sex steroid hormones is mediated through modulation in glycolysis-related transporters and enzymes. Cell Tissue Res 354(3):861–868PubMedCrossRefGoogle Scholar
  37. 37.
    Oliveira PF, Alves MG, Rato L, Laurentino S, Silva J, Sá R, Barros A, Sousa M, Carvalho RA, Cavaco JE (2012) Effect of insulin deprivation on metabolism and metabolism-associated gene transcript levels of in vitro cultured human Sertoli cells. Biochim Biophys Acta 1820(2):84–89PubMedCrossRefGoogle Scholar
  38. 38.
    Grootegoed J, Oonk R, Jansen R, Van der Molen H (1986) Metabolism of radiolabelled energy-yielding substrates by rat Sertoli cells. J Reprod Fertil 77(1):109–118PubMedCrossRefGoogle Scholar
  39. 39.
    Galardo MN, Regueira M, Riera MF, Pellizzari EH, Cigorraga SB, Meroni SB (2014) Lactate regulates rat male germ cell function through reactive oxygen species. PLoS One 9(1):e88024PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Erkkilä K, Aito H, Aalto K, Pentikäinen V, Dunkel L (2002) Lactate inhibits germ cell apoptosis in the human testis. Mol Hum Reprod 8(2):109–117PubMedCrossRefGoogle Scholar
  41. 41.
    Murphy CJ, Richburg JH (2014) Implications of Sertoli cell induced germ cell apoptosis to testicular pathology. Spermatogenesis 4(2):e979110PubMedCrossRefGoogle Scholar
  42. 42.
    Xiong W, Wang H, Wu H, Chen Y, Han D (2009) Apoptotic spermatogenic cells can be energy sources for Sertoli cells. Reproduction 137(3):469–479PubMedCrossRefGoogle Scholar
  43. 43.
    Jesus TT, Bernardino RL, Martins AD, Sá R, Sousa M, Alves MG, Oliveira PF (2014) Aquaporin-4 as a molecular partner of cystic fibrosis transmembrane conductance regulator in rat Sertoli cells. Biochem Biophys Res Commun 446(4):1017–1021PubMedCrossRefGoogle Scholar
  44. 44.
    Jesus TT, Bernardino RL, Martins AD, Sá R, Sousa M, Alves MG, Oliveira PF (2014) Aquaporin-9 is expressed in rat Sertoli cells and interacts with the cystic fibrosis transmembrane conductance regulator. IUBMB Life 66(9):639–644. https://doi.org/10.1002/iub.1312 PubMedCrossRefGoogle Scholar
  45. 45.
    Hardie DG (2003) Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 144(12):5179–5183PubMedCrossRefGoogle Scholar
  46. 46.
    Cheung PC, Davies SP, Hardie DG, Carling D (2000) Characterization of AMP-activated protein kinase γ-subunit isoforms and their role in AMP binding. Biochem J 346(3):659–669PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Stapleton D, Mitchelhill KI, Gao G, Widmer J, Michell BJ, Teh T, House CM, Fernandez CS, Cox T, Witters LA (1996) Mammalian AMP-activated protein kinase subfamily. J Biol Chem 271(2):611–614PubMedCrossRefGoogle Scholar
  48. 48.
    Thornton C, Snowden MA, Carling D (1998) Identification of a novel AMP-activated protein kinase β subunit isoform that is highly expressed in skeletal muscle. J Biol Chem 273(20):12443–12450PubMedCrossRefGoogle Scholar
  49. 49.
    Hardie DG (2004) The AMP-activated protein kinase pathway–new players upstream and downstream. J Cell Sci 117(23):5479–5487PubMedCrossRefGoogle Scholar
  50. 50.
    Hardie DG (2005) New roles for the LKB1 → AMPK pathway. Curr Opin Cell Biol 17(2):167–173PubMedCrossRefGoogle Scholar
  51. 51.
    Hardie DG, Ashford ML (2014) AMPK: regulating energy balance at the cellular and whole body levels. Physiology 29(2):99–107PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Hardie DG, Pan D (2002) Regulation of fatty acid synthesis and oxidation by the AMP-activated protein kinase. Biochem Soc Trans 30(6):1064–1070PubMedCrossRefGoogle Scholar
  53. 53.
    Hardie DG, Sakamoto K (2006) AMPK: a key sensor of fuel and energy status in skeletal muscle. Physiology 21(1):48–60PubMedCrossRefGoogle Scholar
  54. 54.
    Hardie DG, Hawley SA (2001) AMP-activated protein kinase: the energy charge hypothesis revisited. BioEssays 23(12):1112–1119PubMedCrossRefGoogle Scholar
  55. 55.
    Ceddia RB, Sweeney G (2004) Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells. J Physiol 555(2):409–421PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Putman CT, Kiricsi M, Pearcey J, MacLean IM, Bamford JA, Murdoch GK, Dixon WT, Pette D (2003) AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions. J Physiol 551(1):169–178PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Smith AC, Bruce CR, Dyck DJ (2005) AMP kinase activation with AICAR simultaneously increases fatty acid and glucose oxidation in resting rat soleus muscle. J Physiol 565(2):537–546PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17(1):113–124PubMedCrossRefGoogle Scholar
  59. 59.
    Galardo MN, Riera MF, Pellizzari EH, Cigorraga SB, Meroni SB (2007) The AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-bD-ribonucleoside, regulates lactate production in rat Sertoli cells. J Mol Endocrinol 39(4):279–288PubMedCrossRefGoogle Scholar
  60. 60.
    Riera MF, Galardo MN, Pellizzari EH, Meroni SB, Cigorraga SB (2009) Molecular mechanisms involved in Sertoli cell adaptation to glucose deprivation. Am J Physiol Endocrinol Metab 297(4):E907–E914PubMedCrossRefGoogle Scholar
  61. 61.
    Tartarin P, Guibert E, Touré A, Ouiste C, Leclerc J, Sanz N, Brière S, Dacheux J-L, Delaleu B, McNeilly JR (2012) Inactivation of AMPKα1 induces asthenozoospermia and alters spermatozoa morphology. Endocrinology 153(7):3468–3481PubMedCrossRefGoogle Scholar
  62. 62.
    Bertoldo MJ, Guibert E, Faure M, Guillou F, Ramé C, Nadal-Desbarats L, Foretz M, Viollet B, Dupont J, Froment P (2016) Specific deletion of AMP-activated protein kinase (α1AMPK) in mouse Sertoli cells modifies germ cell quality. Mol Cell Endocrinol 423:96–112PubMedCrossRefGoogle Scholar
  63. 63.
    Boussouar F, Benahmed M (1999) Epidermal growth factor regulates glucose metabolism through lactate dehydrogenase A messenger ribonucleic acid expression in cultured porcine Sertoli cells. Biol Reprod 61(4):1139–1145PubMedCrossRefGoogle Scholar
  64. 64.
    Meroni S, Riera M, Pellizzari E, Cigorraga S (2002) Regulation of rat Sertoli cell function by FSH: possible role of phosphatidylinositol 3-kinase/protein kinase B pathway. J Endocrinol 174(2):195–204PubMedCrossRefGoogle Scholar
  65. 65.
    Nehar D, Mauduit C, Boussouar F, Benahmed M (1998) Interleukin 1α stimulates lactate dehydrogenase A expression and lactate production in cultured porcine Sertoli cells. Biol Reprod 59(6):1425–1432PubMedCrossRefGoogle Scholar
  66. 66.
    Rato L, Alves MG, Socorro S, Carvalho RA, Cavaco JE, Oliveira PF (2012) Metabolic modulation induced by oestradiol and DHT in immature rat Sertoli cells cultured in vitro. Biosci Rep 32(1):61–69PubMedCrossRefGoogle Scholar
  67. 67.
    Regueira M, Artagaveytia SL, Galardo MN, Pellizzari EH, Cigorraga SB, Meroni SB, Riera MF (2015) Novel molecular mechanisms involved in hormonal regulation of lactate production in Sertoli cells. Reproduction 150(4):311–321PubMedCrossRefGoogle Scholar
  68. 68.
    Riera MF, Galardo MN, Pellizzari EH, Meroni SB, Cigorraga SB (2007) Participation of phosphatidyl inositol 3-kinase/protein kinase B and ERK1/2 pathways in interleukin-1β stimulation of lactate production in Sertoli cells. Reproduction 133(4):763–773PubMedCrossRefGoogle Scholar
  69. 69.
    Rocha CS, Martins AD, Rato L, Silva BM, Oliveira PF, Alves MG (2014) Melatonin alters the glycolytic profile of Sertoli cells: implications for male fertility. Mol Hum Reprod 20(11):1067–1076PubMedCrossRefGoogle Scholar
  70. 70.
    Monaco L, Conti M (1986) Localization of adenosine receptors in rat testicular cells. Biol Reprod 35(2):258–266PubMedCrossRefGoogle Scholar
  71. 71.
    Gelain DP, De Souza LF, Bernard EA (2003) Extracellular purines from cells of seminiferous tubules. Mol Cell Biochem 245(1):1–9PubMedCrossRefGoogle Scholar
  72. 72.
    Newby AC (1984) Adenosine and the concept of ‘retaliatory metabolites’. Trends Biochem Sci 9(2):42–44CrossRefGoogle Scholar
  73. 73.
    Bjelobaba I, Janjic MM, Stojilkovic SS (2015) Purinergic signaling pathways in endocrine system. Auton Neurosci 191:102–116PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Conti M, Boitani C, Demanno D, Migliaccio S, Monaco L, Szymeczek C (1989) Characterization and function of adenosine receptors in the testisa. Ann N Y Acad Sci 564(1):39–47PubMedCrossRefGoogle Scholar
  75. 75.
    Conti M, Culler MD, Negro-Vilar A (1988) Adenosine receptor-dependent modulation of inhibin secretion in cultured immature rat Sertoli cells. Mol Cell Endocrinol 59(3):255–259PubMedCrossRefGoogle Scholar
  76. 76.
    Meroni S, Cánepa D, Pellizzari E, Schteingart H, Cigorraga S (1998) Effects of purinergic agonists on aromatase and gamma-glutamyl transpeptidase activities and on transferrin secretion in cultured Sertoli cells. J Endocrinol 157(2):275–283PubMedCrossRefGoogle Scholar
  77. 77.
    Monaco L, Toscano M, Conti M (1984) Purine modulation of the hormonal response of the rat Sertoli cell in culture. Endocrinology 115(4):1616–1624PubMedCrossRefGoogle Scholar
  78. 78.
    Kato R, Maeda T, Akaike T, Tamai I (2005) Nucleoside transport at the blood-testis barrier studied with primary-cultured sertoli cells. J Pharmacol Exp Ther 312(2):601–608PubMedCrossRefGoogle Scholar
  79. 79.
    Galardo M, Riera M, Pellizzari E, Sobarzo C, Scarcelli R, Denduchis B, Lustig L, Cigorraga S, Meroni S (2010) Adenosine regulates Sertoli cell function by activating AMPK. Mol Cell Endocrinol 330(1):49–58PubMedCrossRefGoogle Scholar
  80. 80.
    Biswas S, Mukherjee R, Tapryal N, Singh AK, Mukhopadhyay CK (2013) Insulin regulates hypoxia-inducible factor-1α transcription by reactive oxygen species sensitive activation of Sp1 in 3T3-L1 preadipocyte. PLoS One 8(4):e62128PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Chan DA, Sutphin PD, Denko NC, Giaccia AJ (2002) Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1α. J Biol Chem 277(42):40112–40117PubMedCrossRefGoogle Scholar
  82. 82.
    Kietzmann T, Cornesse Y, Brechtel K, Modaressi S, Jungermann K (2001) Perivenous expression of the mRNA of the three hypoxia-inducible factor α-subunits, HIF1α, HIF2α and HIF3α, in rat liver. Biochem J 354(3):531–537PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Wenger RH (2002) Cellular adaptation to hypoxia: O2-sensing protein hydroxylases, hypoxia-inducible transcription factors, and O2-regulated gene expression. FASEB J 16(10):1151–1162PubMedCrossRefGoogle Scholar
  84. 84.
    Fukuda R, Hirota K, Fan F, Do Jung Y, Ellis LM, Semenza GL (2002) Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem 277(41):38205–38211PubMedCrossRefGoogle Scholar
  85. 85.
    Laughner E, Taghavi P, Chiles K, Mahon PC, Semenza GL (2001) HER2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: novel mechanism for HIF-1-mediated vascular endothelial growth factor expression. Mol Cell Biol 21(12):3995–4004PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Treins C, Giorgetti-Peraldi S, Murdaca J, Semenza GL, Van Obberghen E (2002) Insulin stimulates hypoxia-inducible factor 1 through a phosphatidylinositol 3-kinase/target of rapamycin-dependent signaling pathway. J Biol Chem 277(31):27975–27981PubMedCrossRefGoogle Scholar
  87. 87.
    Hu C-J, Sataur A, Wang L, Chen H, Simon MC (2007) The N-terminal transactivation domain confers target gene specificity of hypoxia-inducible factors HIF-1α and HIF-2α. Mol Biol Cell 18(11):4528–4542PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Hu C-J, Wang L-Y, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biol 23(24):9361–9374PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Wang V, Davis DA, Haque M, Huang LE, Yarchoan R (2005) Differential gene up-regulation by hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in HEK293T cells. Cancer Res 65(8):3299–3306PubMedCrossRefGoogle Scholar
  90. 90.
    Gordan JD, Bertout JA, C-J H, Diehl JA, Simon MC (2007) HIF-2α promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11(4):335–347PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Raval RR, Lau KW, Tran MG, Sowter HM, Mandriota SJ, Li J-L, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ (2005) Contrasting properties of hypoxia-inducible factor 1 (HIF-1) and HIF-2 in von Hippel-Lindau-associated renal cell carcinoma. Mol Cell Biol 25(13):5675–5686PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Gruber M, Mathew LK, Runge AC, Garcia JA, Simon MC (2010) EPAS1 is required for spermatogenesis in the postnatal mouse testis. Biol Reprod 82(6):1227–1236PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Guven A, Ickin M, Uzun O, Bakar C, Gulec Balbay E, Balbay O (2014) Erdosteine protects rat testis tissue from hypoxic injury by reducing apoptotic cell death. Andrologia 46(1):50–58PubMedCrossRefGoogle Scholar
  94. 94.
    Zimmermann C, Stévant I, Borel C, Conne B, Pitetti J-L, Calvel P, Kaessmann H, Jégou B, Chalmel F, Nef S (2015) Research resource: the dynamic transcriptional profile of sertoli cells during the progression of spermatogenesis. Mol Endocrinol 29(4):627–642PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Galardo MN, Gorga A, Merlo JP, Regueira M, Pellizzari EH, Cigorraga SB, Riera MF, Meroni SB (2017) Participation of HIFs in the regulation of Sertoli cell lactate production. Biochimie 132:9–18PubMedCrossRefGoogle Scholar
  96. 96.
    Firth JD, Ebert BL, Ratcliffe PJ (1995) Hypoxic regulation of lactate dehydrogenase A interaction between hypoxia-inducible factor 1 and cAMP response elements. J Biol Chem 270(36):21021–21027PubMedCrossRefGoogle Scholar
  97. 97.
    Hayashi M, Sakata M, Takeda T, Yamamoto T, Okamoto Y, Sawada K, Kimura A, Minekawa R, Tahara M, Tasaka K (2004) Induction of glucose transporter 1 expression through hypoxia-inducible factor 1α under hypoxic conditions in trophoblast-derived cells. J Endocrinol 183(1):145–154PubMedCrossRefGoogle Scholar
  98. 98.
    Luo W, Hu H, Chang R, Zhong J, Knabel M, O’Meally R, Cole RN, Pandey A, Semenza GL (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 145(5):732–744PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Jutte NH, Eikvar L, Levy F, Hansson V (1985) Metabolism of palmitate in cultured rat Sertoli cells. J Reprod Fertil 73(2):497–503PubMedCrossRefGoogle Scholar
  100. 100.
    Issemann I, Green S (1990) Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347(6294):645–650PubMedCrossRefGoogle Scholar
  101. 101.
    Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ, Grimaldi PA, Kadowaki T, Lazar MA, O’Rahilly S (2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev 58(4):726–741PubMedCrossRefGoogle Scholar
  102. 102.
    Green S, Wahli W (1994) Peroxisome proliferator-activated receptors: finding the orphan a home. Mol Cell Endocrinol 100(1):149–153PubMedCrossRefGoogle Scholar
  103. 103.
    Krey G, Braissant O, L’Horset F, Kalkhoven E, Perroud M, Parker MG, Wahli W (1997) Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol 11(6):779–791PubMedCrossRefGoogle Scholar
  104. 104.
    Burkart EM, Sambandam N, Han X, Gross RW, Courtois M, Gierasch CM, Shoghi K, Welch MJ, Kelly DP (2007) Nuclear receptors PPARβ/δ and PPARα direct distinct metabolic regulatory programs in the mouse heart. J Clin Invest 117(12):3930–3939PubMedPubMedCentralGoogle Scholar
  105. 105.
    Chawla A, Schwarz EJ, Dimaculangan DD, Lazar MA (1994) Peroxisome proliferator-activated receptor (PPAR) gamma: adipose-predominant expression and induction early in adipocyte differentiation. Endocrinology 135(2):798–800PubMedCrossRefGoogle Scholar
  106. 106.
    Jump DB, Botolin D, Wang Y, Xu J, Christian B, Demeure O (2005) Fatty acid regulation of hepatic gene transcription. J Nutr 135(11):2503–2506PubMedCrossRefGoogle Scholar
  107. 107.
    Tontonoz P, Hu E, Spiegelman BM (1994) Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor. Cell 79(7):1147–1156PubMedCrossRefGoogle Scholar
  108. 108.
    Wang Y-X, Lee C-H, Tiep S, Ruth TY, Ham J, Kang H, Evans RM (2003) Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity. Cell 113(2):159–170PubMedCrossRefGoogle Scholar
  109. 109.
    Kliewer SA, Xu HE, Lambert MH, Willson TM (2000) Peroxisome proliferator-activated receptors: from genes to physiology. Recent Prog Horm Res 56:239–263CrossRefGoogle Scholar
  110. 110.
    Braissant O, Foufelle F, Scotto C, Dauça M, Wahli W (1996) Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha,-beta, and-gamma in the adult rat. Endocrinology 137(1):354–366PubMedCrossRefGoogle Scholar
  111. 111.
    Thomas K, Sung D, Chen X, Thompson W, Chen Y, McCarrey J, Walker W, Griswold M (2010) Developmental patterns of PPAR and RXR gene expression during spermatogenesis. Front Biosci (Elite Ed) 3:1209–1220Google Scholar
  112. 112.
    Regueira M, Riera MF, Galardo M, Pellizzari E, Cigorraga S, Meroni S (2014) Activation of PPAR α and PPAR β/δ regulates Sertoli cell metabolism. Mol Cell Endocrinol 382(1):271–281PubMedCrossRefGoogle Scholar
  113. 113.
    Gorga A, Rindone G, Regueira M, Pellizzari E, Cigorraga S, Riera MF, Meroni SB (2017) PPARγ activation regulates lipid droplet formation and lactate production in rat Sertoli cells. Cell Tissue Res. https://doi.org/10.1007/s00441-017-2615-y
  114. 114.
    Hamilton BE, Ventura SJ (2006) Fertility and abortion rates in the United States, 1960–2002. Int J Androl 29(1):34–45PubMedCrossRefGoogle Scholar
  115. 115.
    World Health Organization (2000) Obesity: preventing and managing the global epidemic, WHO technical report series, vol vol 894. World Health Organization, GenèveGoogle Scholar
  116. 116.
    Crisóstomo L, Sousa M, Alves MG, Oliveira PF (2017) The burden of metabolic diseases on male reproductive health. Int J Diabetol Vasc Dis Res 5(1e):1–2Google Scholar
  117. 117.
    Chambers T, Richard R (2015) The impact of obesity on male fertility. Hormones 14:563–568PubMedGoogle Scholar
  118. 118.
    Alves MG, Martins AD, Cavaco JE, Socorro S, Oliveira PF (2013) Diabetes, insulin-mediated glucose metabolism and Sertoli/blood-testis barrier function. Tissue barriers 1(2):e23992. https://doi.org/10.4161/tisb.23992 PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Cai L, Chen S, Evans T, Deng DX, Mukherjee K, Chakrabarti S (2000) Apoptotic germ-cell death and testicular damage in experimental diabetes: prevention by endothelin antagonism. Urol Res 28(5):342–347PubMedCrossRefGoogle Scholar
  120. 120.
    Belanger C, Dupont P, Tchernof A (2002) Adipose tissue intracrinology: potential importance of local androgen/estrogen metabolism in the regulation of adiposity. Horm Metab Res 34(11/12):737–745PubMedCrossRefGoogle Scholar
  121. 121.
    Roumaud P, Martin LJ (2015) Roles of leptin, adiponectin and resistin in the transcriptional regulation of steroidogenic genes contributing to decreased Leydig cells function in obesity. Horm Mol Biol Clin Investig 24(1):25–45. https://doi.org/10.1515/hmbci-2015-0046 PubMedGoogle Scholar
  122. 122.
    Rato L, Alves MG, Duarte AI, Santos MS, Moreira PI, Cavaco JE, Oliveira PF (2015) Testosterone deficiency induced by progressive stages of diabetes mellitus impairs glucose metabolism and favors glycogenesis in mature rat Sertoli cells. Int J Biochem Cell Biol 66:1–10PubMedCrossRefGoogle Scholar
  123. 123.
    Oliveira PF, Sousa M, Silva BM, Monteiro MP, Alves MG (2017) Obesity, energy balance and spermatogenesis. Reproduction 153(6):R173–R185. https://doi.org/10.1530/rep-17-0018 PubMedCrossRefGoogle Scholar
  124. 124.
    Reis M, Moreira AC, Sousa M, Mathur PP, Oliveira PF, Alves MG (2015) Sertoli cell as a model in male reproductive toxicology: advantages and disadvantages. J Appl Toxicol 35(8):870–883PubMedCrossRefGoogle Scholar
  125. 125.
    Wallace WHB, Shalet SM, Crowne E, Morris-Jones P, Gattamaneni H, Price DA (1989) Gonadal dysfunction due to cis-platinum. Med Pediatr Oncol 17(5–6):409–413PubMedGoogle Scholar
  126. 126.
    Monsees T, Franz M, Gebhardt S, Winterstein U, Schill WB, Hayatpour J (2000) Sertoli cells as a target for reproductive hazards. Andrologia 32(4–5):239–246PubMedCrossRefGoogle Scholar
  127. 127.
    Wiebe JP, Kowalik A, Gallardi RL, Egeler O, Clubb BH (2000) Glycerol disrupts tight junction-associated actin microfilaments, occludin, and microtubules in Sertoli cells. J Androl 21(5):625–635PubMedGoogle Scholar
  128. 128.
    Raychoudhury SS, Blake CA, Millette CF (1999) Toxic effects of octylphenol on cultured rat spermatogenic cells and Sertoli cells. Toxicol Appl Pharmacol 157(3):192–202PubMedCrossRefGoogle Scholar
  129. 129.
    Alves MG, Neuhaus-Oliveira A, Moreira PI, Socorro S, Oliveira PF (2013) Exposure to 2,4-dichlorophenoxyacetic acid alters glucose metabolism in immature rat Sertoli cells. Reprod Toxicol 38:81–88. https://doi.org/10.1016/j.reprotox.2013.03.005 PubMedCrossRefGoogle Scholar
  130. 130.
    Bizarro P, Acevedo S, Niño-Cabrera G, Mussali-Galante P, Pasos F, Avila-Costa MR, Fortoul TI (2003) Ultrastructural modifications in the mitochondrion of mouse Sertoli cells after inhalation of lead, cadmium or lead–cadmium mixture. Reprod Toxicol 17(5):561–566PubMedCrossRefGoogle Scholar
  131. 131.
    Alves MG, Jesus TT, Sousa M, Goldberg E, Silva BM, Oliveira PF (2016) Male fertility and obesity: are ghrelin, leptin and glucagon-like peptide-1 pharmacologically relevant? Curr Pharm Des 22(7):783–791. https://doi.org/10.2174/1381612822666151209151550 PubMedCrossRefGoogle Scholar
  132. 132.
    Martins AD, Moreira AC, Sá R, Monteiro MP, Sousa M, Carvalho RA, Silva BM, Oliveira PF, Alves MG (2015) Leptin modulates human Sertoli cells acetate production and glycolytic profile: a novel mechanism of obesity-induced male infertility? Biochim Biophys Acta 1852(9):1824–1832PubMedCrossRefGoogle Scholar
  133. 133.
    Martins AD, Sá R, Monteiro MP, Barros A, Sousa M, Carvalho RA, Silva BM, Oliveira PF, Alves MG (2016) Ghrelin acts as energy status sensor of male reproduction by modulating Sertoli cells glycolytic metabolism and mitochondrial bioenergetics. Mol Cell Endocrinol 434:199–209PubMedCrossRefGoogle Scholar
  134. 134.
    Wiebe JP, Barr KJ (1984) The control of male fertility by 1,2,3-trihydroxypropane (THP;glycerol): rapid arrest of spermatogenesis without altering libido, accessory organs, gonadal steroidogenesis, and serum testosterone, LH and FSH. Contraception 29(3):291–302PubMedCrossRefGoogle Scholar
  135. 135.
    Rodríguez A, Catalán V, Gómez-Ambrosi J, García-Navarro S, Rotellar F, Valentí V, Silva C, Gil MJ, Salvador J, Burrell MA (2011) Insulin-and leptin-mediated control of aquaglyceroporins in human adipocytes and hepatocytes is mediated via the PI3K/Akt/mTOR signaling cascade. J Clin Endocrinol Metab 96(4):E586–E597PubMedCrossRefGoogle Scholar
  136. 136.
    Lin EC (1977) Glycerol utilization and its regulation in mammals. Annu Rev Biochem 46:765–795. https://doi.org/10.1146/annurev.bi.46.070177.004001 PubMedCrossRefGoogle Scholar
  137. 137.
    Hagstrom-Toft E, Enoksson S, Moberg E, Bolinder J, Arner P (1997) Absolute concentrations of glycerol and lactate in human skeletal muscle, adipose tissue, and blood. Am J Phys 273(3 Pt 1):E584–E592Google Scholar
  138. 138.
    Yeung CH, Callies C, Tuttelmann F, Kliesch S, Cooper TG (2010) Aquaporins in the human testis and spermatozoa - identification, involvement in sperm volume regulation and clinical relevance. Int J Androl 33(4):629–641. https://doi.org/10.1111/j.1365-2605.2009.00998.x PubMedGoogle Scholar
  139. 139.
    Vestergaard ET, Moller N, Jorgensen JO (2013) Acute peripheral tissue effects of ghrelin on interstitial levels of glucose, glycerol, and lactate: a microdialysis study in healthy human subjects. Am J Physiol Endocrinol Metab 304(12):E1273–E1280. https://doi.org/10.1152/ajpendo.00662.2012 PubMedCrossRefGoogle Scholar
  140. 140.
    Lorenzi T, Meli R, Marzioni D, Morroni M, Baragli A, Castellucci M, Gualillo O, Muccioli G (2009) Ghrelin: a metabolic signal affecting the reproductive system. Cytokine Growth Factor Rev 20(2):137–152PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2018

Authors and Affiliations

  • Luís Crisóstomo
    • 1
    • 2
    • 3
  • Marco G. Alves
    • 1
  • Agostina Gorga
    • 4
  • Mário Sousa
    • 1
    • 5
  • María F. Riera
    • 4
  • María N. Galardo
    • 4
  • Silvina B. Meroni
    • 4
    Email author
  • Pedro F. Oliveira
    • 6
    • 7
    • 8
    • 9
  1. 1.Unit for Multidisciplinary Research in Biomedicine (UMIB), Laboratory of Cell Biology, Department of Microscopy, Institute of Biomedical Sciences Abel Salazar (ICBAS)University of PortoPortoPortugal
  2. 2.Department of Genetics, Faculty of Medicine (FMUP)University of PortoPortoPortugal
  3. 3.i3S-Instituto de Investigação e Inovação em SaúdeUniversity of PortoPortoPortugal
  4. 4.CONICET-FEI-División de Endocrinología, Hospital de Niños Ricardo GutiérrezCentro de Investigaciones Endocrinológicas “Dr César Bergadá”Ciudad Autónoma de Buenos AiresArgentina
  5. 5.Centre for Reproductive Genetics Prof. Alberto BarrosPortoPortugal
  6. 6.Department of Microscopy, Laboratory of Cell Biology and Unit for Multidisciplinary Research in Biomedicine (UMIB), Institute of Biomedical Sciences Abel Salazar (ICBAS)University of PortoPortoPortugal
  7. 7.Department of Genetics, Faculty of MedicineUniversity of PortoPortoPortugal
  8. 8.i3S - Instituto de Investigação e Inovação em SaúdeUniversity of PortoPortoPortugal
  9. 9.Department of Biosciences, Biotechnologies and BiopharmaceuticsUniversity of Bari “Aldo Moro”BariItaly

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