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BioMed Research International
Volume 2017 (2017), Article ID 3756089, 13 pages
https://doi.org/10.1155/2017/3756089
Research Article

Loss of PI3K p110α in the Adipose Tissue Results in Infertility and Delayed Puberty Onset in Male Mice

1Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, NY, USA
2Graduate Program in Neuroscience, State University of New York at Stony Brook, Stony Brook, NY, USA
3Department of Veterans Affairs Medical Center, Northport, NY, USA

Correspondence should be addressed to Maricedes Acosta-Martínez

Received 11 October 2016; Revised 5 January 2017; Accepted 22 January 2017; Published 5 March 2017

Academic Editor: Leon Spicer

Copyright © 2017 Victoria L. Boughton Nelson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. C. M. Kusminski, P. E. Bickel, and P. E. Scherer, “Targeting adipose tissue in the treatment of obesity-associated diabetes,” Nature Reviews Drug Discovery, vol. 15, no. 9, pp. 639–660, 2016. View at Publisher · View at Google Scholar · View at Scopus
  2. P. Roumaud and L. J. Martin, “Roles of leptin, adiponectin and resistin in the transcriptional regulation of steroidogenic genes contributing to decreased Leydig cells function in obesity,” Hormone Molecular Biology and Clinical Investigation, vol. 24, no. 1, pp. 25–45, 2015. View at Publisher · View at Google Scholar · View at Scopus
  3. J. F. Kawwass, R. Summer, and C. B. Kallen, “Direct effects of leptin and adiponectin on peripheral reproductive tissues: a critical review,” Molecular Human Reproduction, vol. 21, no. 8, pp. 617–632, 2015. View at Publisher · View at Google Scholar · View at Scopus
  4. S. Moschos, J. L. Chan, and C. S. Mantzoros, “Leptin and reproduction: a review,” Fertility and Sterility, vol. 77, no. 3, pp. 433–444, 2002. View at Publisher · View at Google Scholar · View at Scopus
  5. M. Acosta-Martínez, “PI3K: an attractive candidate for the central integration of metabolism and reproduction,” Frontiers in Endocrinology, vol. 2, article no. 110, 2011. View at Publisher · View at Google Scholar · View at Scopus
  6. A. E. Buyken, N. Karaolis-Danckert, and T. Remer, “Association of prepubertal body composition in healthy girls and boys with the timing of early and late pubertal markers,” American Journal of Clinical Nutrition, vol. 89, no. 1, pp. 221–230, 2009. View at Publisher · View at Google Scholar · View at Scopus
  7. J. M. Lee, R. Wasserman, N. Kaciroti et al., “Timing of puberty in overweight versus obese boys,” Pediatrics, vol. 137, no. 2, Article ID e20150164, 2016. View at Publisher · View at Google Scholar · View at Scopus
  8. N. O. Palmer, H. W. Bakos, T. Fullston, and M. Lane, “Impact of obesity on male fertility, sperm function and molecular composition,” Spermatogenesis, vol. 2, no. 4, pp. 253–263, 2014. View at Publisher · View at Google Scholar
  9. M. A. Sanchez-Garrido and M. Tena-Sempere, “Metabolic control of puberty: roles of leptin and kisspeptins,” Hormones and Behavior, vol. 64, no. 2, pp. 187–194, 2013. View at Publisher · View at Google Scholar · View at Scopus
  10. S. S. Du Plessis, S. Cabler, D. A. McAlister, E. Sabanegh, and A. Agarwal, “The effect of obesity on sperm disorders and male infertility,” Nature Reviews Urology, vol. 7, no. 3, pp. 153–161, 2010. View at Publisher · View at Google Scholar · View at Scopus
  11. P. G. Cohen, “Aromatase, adiposity, aging and disease. The hypogonadal-metabolic-atherogenic-disease and aging connection,” Medical Hypotheses, vol. 56, no. 6, pp. 702–708, 2001. View at Publisher · View at Google Scholar · View at Scopus
  12. S. A. Kaplan, A. G. Meehan, and A. Shah, “The age related decrease in testosterone is significantly exacerbated in obese men with the metabolic syndrome. what are the implications for the relatively high incidence of erectile dysfunction observed in these men?” Journal of Urology, vol. 176, no. 4, pp. 1524–1528, 2006. View at Publisher · View at Google Scholar · View at Scopus
  13. L. C. Foukas, M. Claret, W. Pearce et al., “Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation,” Nature, vol. 441, no. 7091, pp. 366–370, 2006. View at Publisher · View at Google Scholar · View at Scopus
  14. Z. A. Knight, B. Gonzalez, M. E. Feldman et al., “A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling,” Cell, vol. 125, no. 4, pp. 733–747, 2006. View at Publisher · View at Google Scholar · View at Scopus
  15. V. L. B. Nelson, Y.-P. Jiang, K. G. Dickman, L. M. Ballou, and R. Z. Lin, “Adipose tissue insulin resistance due to loss of PI3K p110α leads to decreased energy expenditure and obesity,” American Journal of Physiology—Endocrinology and Metabolism, vol. 306, no. 10, pp. E1205–E1216, 2014. View at Publisher · View at Google Scholar · View at Scopus
  16. R. Aziz, M. Beymer, A. L. Negrón et al., “Galanin-like peptide (GALP) neurone-specific phosphoinositide 3-kinase signalling regulates GALP mRNA Levels in the hypothalamus of males and luteinising hormone levels in both sexes,” Journal of Neuroendocrinology, vol. 26, no. 7, pp. 426–438, 2014. View at Publisher · View at Google Scholar · View at Scopus
  17. M. Beymer, A. L. Negrón, G. Yu et al., “Kisspeptin cell-specific PI3K signaling regulates hypothalamic kisspeptin expression and participates in the regulation of female fertility,” American Journal of Physiology—Endocrinology and Metabolism, vol. 307, no. 11, pp. E969–E982, 2014. View at Publisher · View at Google Scholar · View at Scopus
  18. E. Ciraolo, F. Morello, R. M. Hobbs et al., “Essential role of the p110β subunit of phosphoinositide 3-OH kinase in male fertility,” Molecular Biology of the Cell, vol. 21, no. 5, pp. 704–711, 2010. View at Publisher · View at Google Scholar · View at Scopus
  19. J. Guillermet-Guibert, L. B. Smith, G. Halet et al., “Novel role for p110β PI 3-kinase in male fertility through regulation of androgen receptor activity in sertoli cells,” PLoS Genetics, vol. 11, no. 7, Article ID e1005304, 2015. View at Publisher · View at Google Scholar · View at Scopus
  20. M. Acosta-Martinez, V. L. B. Nelson, A. L. Negron, and R. Z. Lin, “Loss of p110 alpha in the adipose tissue results in infertility and delayed puberty onset in male mice,” in Proceedings of the Endocrine Society's 97th Annual Meeting and Expo, San Diego, Calif, USA, March 2015.
  21. C. Barlow, M. Schroeder, J. Lekstrom-Himes et al., “Targeted expression of Cre recombinase to adipose tissue of transgenic mice directs adipose-specific excision of loxP-flanked gene segments,” Nucleic Acids Research, vol. 25, no. 12, pp. 2543–2545, 1997. View at Publisher · View at Google Scholar · View at Scopus
  22. H. M. Hoffmann, A. Tamrazian, H. Xie, M. I. Pérez-Millán, A. S. Kauffman, and P. L. Mellon, “Heterozygous deletion of ventral anterior homeobox (Vax1) causes subfertility in mice,” Endocrinology, vol. 155, no. 10, pp. 4043–4053, 2014. View at Publisher · View at Google Scholar · View at Scopus
  23. X. Wu, R. Arumugam, N. Zhang, and M. M. Lee, “Androgen profiles during pubertal Leydig cell development in mice,” Reproduction, vol. 140, no. 1, pp. 113–121, 2010. View at Publisher · View at Google Scholar · View at Scopus
  24. M. Bertan Yilmaz, A. Wolfe, H. Zhao, D. C. Brooks, and S. E. Bulun, “Aromatase promoter I.f is regulated by progesterone receptor in mouse hypothalamic neuronal cell lines,” Journal of Molecular Endocrinology, vol. 47, no. 1, pp. 69–80, 2011. View at Publisher · View at Google Scholar · View at Scopus
  25. C. Wang, Q. Tao, X. Wang, X. Wang, and X. Zhang, “Impact of high-fat diet on liver genes expression profiles in mice model of nonalcoholic fatty liver disease,” Environmental Toxicology and Pharmacology, vol. 45, pp. 52–62, 2016. View at Publisher · View at Google Scholar · View at Scopus
  26. Y. Zhang, K.-Y. Guo, P. A. Diaz, M. Heo, and R. L. Leibel, “Determinants of leptin gene expression in fat depots of lean mice,” American Journal of Physiology—Regulatory, Integrative and Comparative Physiology, vol. 282, no. 1, pp. R226–R234, 2002. View at Publisher · View at Google Scholar · View at Scopus
  27. D. V. Tortoriello, J. McMinn, and S. C. Chua, “Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice,” Endocrinology, vol. 145, no. 3, pp. 1238–1247, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. A. Qin, J. Qin, Y. Jin et al., “DHEA improves the antioxidant capacity of endometrial stromal cells and improves endometrium receptivity via androgen receptor,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 198, pp. 120–126, 2016. View at Publisher · View at Google Scholar · View at Scopus
  29. M. Chen, A. Wolfe, X. Wang, C. Chang, S. Yeh, and S. Radovick, “Generation and characterization of a complete null estrogen receptor α mouse using Cre/LoxP technology,” Molecular and Cellular Biochemistry, vol. 321, no. 1-2, pp. 145–153, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. C. C. Korenbrot, I. T. Huhtaniemi, and R. I. Weiner, “Preputial separation as an external sign of pubertal development in the male rat,” Biology of Reproduction, vol. 17, no. 2, pp. 298–303, 1977. View at Publisher · View at Google Scholar · View at Scopus
  31. C. D. B. Fernandez, F. F. Bellentani, G. S. A. Fernandes et al., “Diet-induced obesity in rats leads to a decrease in sperm motility,” Reproductive Biology and Endocrinology, vol. 9, article 32, 2011. View at Publisher · View at Google Scholar · View at Scopus
  32. A. Olivares, J. P. Méndez, E. Zambrano et al., “Reproductive axis function and gonadotropin microheterogeneity in a male rat model of diet-induced obesity,” General and Comparative Endocrinology, vol. 166, no. 2, pp. 356–364, 2010. View at Publisher · View at Google Scholar · View at Scopus
  33. A. Hoffmann, G.-M. Manjowk, I. V. Wagner et al., “Leptin within the subphysiological to physiological range dose dependently improves male reproductive function in an obesity mouse model,” Endocrinology, vol. 157, no. 6, pp. 2461–2468, 2016. View at Publisher · View at Google Scholar · View at Scopus
  34. M. Tena-Sempere and M. L. Barreiro, “Leptin in male reproduction: the testis paradigm,” Molecular and Cellular Endocrinology, vol. 188, no. 1-2, pp. 9–13, 2002. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Abbasihormozi, A. Shahverdi, A. Kouhkan, J. Cheraghi, A. A. Akhlaghi, and A. Kheimeh, “Relationship of leptin administration with production of reactive oxygen species, sperm DNA fragmentation, sperm parameters and hormone profile in the adult rat,” Archives of Gynecology and Obstetrics, vol. 287, no. 6, pp. 1241–1249, 2013. View at Publisher · View at Google Scholar · View at Scopus
  36. H. M. Behre, M. Simoni, and E. Nieschlag, “Strong association between serum levels of leptin and testosterone in men,” Clinical Endocrinology, vol. 47, no. 2, pp. 237–240, 1997. View at Publisher · View at Google Scholar · View at Scopus
  37. J. Zhao, L. Zhai, Z. Liu, S. Wu, and L. Xu, “Leptin level and oxidative stress contribute to obesity-induced low testosterone in murine testicular tissue,” Oxidative Medicine and Cellular Longevity, vol. 2014, Article ID 190945, 14 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  38. M. A. Sánchez-Garrido, J. M. Castellano, F. Ruiz-Pino et al., “Metabolic programming of puberty: sexually dimorphic responses to early nutritional challenges,” Endocrinology, vol. 154, no. 9, pp. 3387–3400, 2013. View at Publisher · View at Google Scholar · View at Scopus
  39. W. F. Blum, P. Englaro, S. Hanitsch et al., “Plasma leptin levels in healthy children and adolescents: dependence on body mass index, body fat mass, gender, pubertal stage, and testosterone,” The Journal of Clinical Endocrinology & Metabolism, vol. 82, no. 9, pp. 2904–2910, 1997. View at Publisher · View at Google Scholar · View at Scopus
  40. D. R. Mann, A. O. K. Johnson, T. Gimpel, and V. D. Castracane, “Changes in circulating leptin, leptin receptor, and gonadal hormones from infancy until advanced age in humans,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 7, pp. 3339–3345, 2003. View at Publisher · View at Google Scholar · View at Scopus
  41. D. L. Coleman, “Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice,” Diabetologia, vol. 14, no. 3, pp. 141–148, 1978. View at Publisher · View at Google Scholar · View at Scopus
  42. F. F. Chehab, M. E. Lim, and R. Lu, “Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin,” Nature Genetics, vol. 12, no. 3, pp. 318–320, 1996. View at Publisher · View at Google Scholar · View at Scopus
  43. K. Mounzih, R. Lu, and F. F. Chehab, “Leptin treatment rescues the sterility of genetically obese ob/ob males,” Endocrinology, vol. 138, no. 3, pp. 1190–1193, 1997. View at Publisher · View at Google Scholar · View at Scopus
  44. R. S. Ahima, J. Dushay, S. N. Flier, D. Prabakaran, and J. S. Flier, “Leptin accelerates the onset of puberty in normal female mice,” The Journal of Clinical Investigation, vol. 99, no. 3, pp. 391–395, 1997. View at Publisher · View at Google Scholar · View at Scopus
  45. M. Yuan, G. Huang, J. Li et al., “Hyperleptinemia directly affects testicular maturation at different sexual stages in mice, and suppressor of cytokine signaling 3 is involved in this process,” Reproductive Biology and Endocrinology, vol. 12, no. 1, article 15, 2014. View at Publisher · View at Google Scholar · View at Scopus
  46. M. Giusti, R. Guido, S. Valenti, and G. Giordano, “Serum leptin levels in males with delayed puberty during short-term pulsatile GnRH administration,” Journal of Endocrinological Investigation, vol. 22, no. 1, pp. 6–11, 1999. View at Publisher · View at Google Scholar · View at Scopus
  47. A. Giovambattista, M. O. Suescun, C. C. D. L. Nessralla, L. R. França, E. Spinedi, and R. S. Calandra, “Modulatory effects of leptin on leydig cell function of normal and hyperleptinemic rats,” Neuroendocrinology, vol. 78, no. 5, pp. 270–279, 2003. View at Publisher · View at Google Scholar · View at Scopus
  48. M. Tena-Sempere, L. Pinilla, L. C. González, C. Diéguez, F. F. Casanueva, and E. Aguilar, “Leptin inhibits testosterone secretion from adult rat testis in vitro,” The Journal of Endocrinology, vol. 161, no. 2, pp. 211–218, 1999. View at Publisher · View at Google Scholar · View at Scopus
  49. W. A. Banks, R. N. McLay, A. J. Kastin, U. Sarmiento, and S. Scully, “Passage of leptin across the blood-testis barrier,” American Journal of Physiology, vol. 276, no. 6, part 1, pp. E1099–E1104, 1999. View at Google Scholar · View at Scopus
  50. M. Caprio, A. M. Isidori, A. R. Carta, C. Moretti, M. L. Dufau, and A. Fabbri, “Expression of functional leptin receptors in rodent Leydig cells,” Endocrinology, vol. 140, no. 11, pp. 4939–4947, 1999. View at Google Scholar · View at Scopus
  51. P. L. Zamorano, V. B. Mahesh, L. M. De Sevilla, L. P. Chorich, G. K. Bhat, and D. W. Brann, “Expression and localization of the leptin receptor in endocrine and neuroendocrine tissues of the rat,” Neuroendocrinology, vol. 65, no. 3, pp. 223–228, 1997. View at Google Scholar · View at Scopus
  52. T. Ishikawa, H. Fujioka, T. Ishimura, A. Takenaka, and M. Fujisawa, “Expression of leptin and leptin receptor in the testis of fertile and infertile patients,” Andrologia, vol. 39, no. 1, pp. 22–27, 2007. View at Publisher · View at Google Scholar · View at Scopus
  53. D. Landry, F. Cloutier, and L. J. Martin, “Implications of leptin in neuroendocrine regulation of male reproduction,” Reproductive Biology, vol. 13, no. 1, pp. 1–14, 2013. View at Publisher · View at Google Scholar · View at Scopus
  54. M. Tena-Sempere, P. R. Manna, F.-P. Zhang et al., “Molecular mechanisms of leptin action in adult rat testis: potential targets for leptin-induced inhibition of steroidogenesis and pattern of leptin receptor messenger ribonucleic acid expression,” Journal of Endocrinology, vol. 170, no. 2, pp. 413–423, 2001. View at Publisher · View at Google Scholar · View at Scopus
  55. M. A. Sánchez-Garrido, F. Ruiz-Pino, M. Manfredi-Lozano et al., “Obesity-induced hypogonadism in the male: premature reproductive neuroendocrine senescence and contribution of Kiss1-mediated mechanisms,” Endocrinology, vol. 155, no. 3, pp. 1067–1079, 2014. View at Publisher · View at Google Scholar · View at Scopus
  56. W.-J. Yan, Y. Mu, N. Yu et al., “Protective effects of metformin on reproductive function in obese male rats induced by high-fat diet,” Journal of Assisted Reproduction and Genetics, vol. 32, no. 7, pp. 1097–1104, 2015. View at Publisher · View at Google Scholar · View at Scopus
  57. V. A. Giagulli, J. M. Kaufman, and A. Vermeulen, “Pathogenesis of the decreased androgen levels in obese men,” The Journal of Clinical Endocrinology & Metabolism, vol. 79, no. 4, pp. 997–1000, 1994. View at Publisher · View at Google Scholar · View at Scopus
  58. B. T. Akingbemi, “Estrogen regulation of testicular function,” Reproductive Biology and Endocrinology, vol. 3, article 51, 2005. View at Publisher · View at Google Scholar · View at Scopus
  59. S. Carreau, C. Bois, L. Zanatta, F. R. M. B. Silva, H. Bouraima-Lelong, and C. Delalande, “Estrogen signaling in testicular cells,” Life Sciences, vol. 89, no. 15-16, pp. 584–587, 2011. View at Publisher · View at Google Scholar · View at Scopus
  60. E. M. Eddy, T. F. Washburn, D. O. Bunch et al., “Targeted disruption of the estrogen receptor gene in male mice causes alteration of spermatogenesis and infertility,” Endocrinology, vol. 137, no. 11, pp. 4796–4805, 1996. View at Publisher · View at Google Scholar · View at Scopus
  61. M. A. McDevitt, C. Glidewell-Kenney, J. Weiss, P. Chambon, J. L. Jameson, and J. E. Levine, “Estrogen response element-independent estrogen receptor (ER)-α signaling does not rescue sexual behavior but restores normal testosterone secretion in male ERα knockout mice,” Endocrinology, vol. 148, no. 11, pp. 5288–5294, 2007. View at Publisher · View at Google Scholar · View at Scopus
  62. E. F. Rissman, S. R. Wersinger, J. A. Taylor, and D. B. Lubahn, “Estrogen receptor function as revealed by knockout studies: neuroendocrine and behavioral aspects,” Hormones and Behavior, vol. 31, no. 3, pp. 232–243, 1997. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Chen, I. Hsu, A. Wolfe et al., “Defects of prostate development and reproductive system in the estrogen receptor-α null male mice,” Endocrinology, vol. 150, no. 1, pp. 251–259, 2009. View at Publisher · View at Google Scholar · View at Scopus
  64. J. Puri, B. Hutchins, L. L. Bellinger, and P. R. Kramer, “Estrogen and inflammation modulate estrogen receptor alpha expression in specific tissues of the temporomandibular joint,” Reproductive Biology and Endocrinology, vol. 7, article 155, 2009. View at Publisher · View at Google Scholar · View at Scopus
  65. B. T. Akingbemi, R. Ge, C. S. Rosenfeld et al., “Estrogen receptor-α gene deficiency enhances androgen biosynthesis in the mouse Leydig cell,” Endocrinology, vol. 144, no. 1, pp. 84–93, 2003. View at Publisher · View at Google Scholar · View at Scopus
  66. R. Pasquali, F. Casimirri, R. De Iasio et al., “Insulin regulates testosterone and sex hormone-binding globulin concentrations in adult normal weight and obese men,” Journal of Clinical Endocrinology and Metabolism, vol. 80, no. 2, pp. 654–658, 1995. View at Google Scholar · View at Scopus
  67. B. I. Ghanayem, R. Bai, G. E. Kissling, G. Travlos, and U. Hoffler, “Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity,” Biology of Reproduction, vol. 82, no. 1, pp. 96–104, 2010. View at Publisher · View at Google Scholar · View at Scopus
  68. V. Reame, E. Z. Pytlowanciv, D. L. Ribeiro et al., “Obesogenic environment by excess of dietary fats in different phases of development reduces spermatic efficiency of wistar rats at adulthood: correlations with metabolic status,” Biology of Reproduction, vol. 91, no. 6, article no. 151, 2014. View at Publisher · View at Google Scholar · View at Scopus