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Leptin-deficient (ob/ob) mouse ovaries show fatty degeneration, enhanced apoptosis and decreased expression of steroidogenic acute regulatory enzyme

International Journal of Obesity volume 36, pages 1047–1053 (2012)Cite this article

Subjects

Abstract

Objective:

Leptin-deficient (ob/ob) mice are obese and infertile. Dysfunctions of the ovaries are preferentially related to leptin-deficiency.

Design:

Morphological and molecular biological obesity-dependent changes in ob/ob ovaries.

Subjects:

Ovaries were obtained from three-month-old mice either homozygote (ob/ob) and heterozygote (ob/+) or wild-type (C57BL6, WT) for the investigation by light and electron microscopy, as well as for western blot analysis of lectin-like oxidised low density lipoprotein receptor (LOX-1), Toll-like receptor 4 (TLR4), CD36, cleaved caspase-3, microtubule-associated protein light chain 3 (LC3), and the steroidogenic acute regulatory protein (StAR).

Results:

Compared with control ovaries with corpora lutea, ob/ob ovaries lacked corpora lutea, follicular atresia was at a higher rate; lipid droplets accumulated in follicle cells and in the oocyte with damaged mitochondria; the basement membrane of follicles was thickened. LOX-1 and CD36 expressions were comparable for all three groups. Ob/ob ovaries showed significantly higher levels of TLR4 and cleaved caspase-3 than the ones from the control groups. The high LC3-II/I ratio in the WT and ob/+ ovaries was related to the presence of corpora lutea. The StAR protein was lower in the ob/ob ovaries signifying reduced steroidogenesis.

Conclusions:

Excessive lipid storage causes disorders of ovarian function in ob/ob mice. The local lipid overload leads to advanced follicular atresia with apoptosis and defect steroidogenesis. We suggest that the changes in lipid metabolism lead to increased oxidative stress and thereby, they are an important reason of anovulation and infertility.

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References

  1. Swerdloff RS, Batt RA, Bray GA . Reproductive hormonal function in the genetically obese (ob/ob) mouse. Endocrinology 1976; 98: 1339–1364.

    Article  Google Scholar 

  2. Lindström P . The physiology of obese-hyperglycemic mice [ob/ob mice]. ScientificWorldJournal 2007; 7: 666–685.

    Article  Google Scholar 

  3. Mitchell M, Armstrong DT, Robker RL, Norman RJ . Adipokines:implications for female infertility and obesity. Reproduction 2005; 130: 583–597.

    Article  CAS  Google Scholar 

  4. Agarwal SK, Vogel K, Weitsman SR, Magoffin DA . Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and theca cells of the human ovary. J Clin Endocrinol Metab 1999; 84: 1072–1076.

    CAS  PubMed  Google Scholar 

  5. Duggal PS, Ryan NK, Van der Hoek KH, Ritter LJ, Armstrong DT, Magoffin DA et al. Effects of leptin administration and feed restriction on thecal leucocytes in the preovulatory rat ovary and effects of leptin on meiotic maturation, granulosa cell proliferation, steroid hormone and PGE2 release in cultured ovarian follicles. Reproduction 2002; 123: 891–898.

    Article  CAS  Google Scholar 

  6. Barkan D, Hurgin V, Dekel N, Amsterdam A, Rubinstein M . Leptin induces ovulation in GnRH-deficient mice. FASEB J 2005; 19: 133–135.

    Article  CAS  Google Scholar 

  7. Löffler S, Aust G, Köhler U, Spanel-Borowski K . Evidence of leptin expression in normal and polycystic human ovaries. Mol Hum Reprod 2001; 7: 1143–1149.

    Article  Google Scholar 

  8. Garris DR, Garris BL . Genomic modulation of diabetes (db/db) and obese (ob/ob) mutation-induced hypercytolipidemia: cytochemical basis of female reproductive tract involution. Cell Tissue Res 2004; 316: 233–241.

    Article  Google Scholar 

  9. Hamm ML, Bhat GK, Thompson WE, Mann DR . Folliculogenesis is impaired and granulosa cell apoptosis is increased in leptin-deficient mice. Biol of Reprod 2004; 71: 66–72.

    Article  CAS  Google Scholar 

  10. Wisse BE, Kim F, Schwartz MW . Physiology: an integrative view of obesity. Science 2007; 318: 928–929.

    Article  CAS  Google Scholar 

  11. Haluzik M, Colombo C, Gavrilova O, Chua S, Wolf N, Chen M et al. Genetic background (C57BL/6J versus FVB/N) strongly influences the severity of diabetes and insulin resistance in ob/ob mice. Endocrinology 2004; 145: 3258–3264.

    Article  CAS  Google Scholar 

  12. Drel VR, Mashtalir N, Ilnytska O, Shin J, Li F, Lyzogubov VV et al. The leptin-deficient (ob/ob) mouse: a new animal model of peripheral neuropathy of type 2 diabetes and obesity. Diabetes 2006; 55: 3335–3343.

    Article  CAS  Google Scholar 

  13. Garris DR . Ovarian hypercytolipidemia induced by obese (ob/ob) and diabetes (db7 DB) mutations: basis of female reproductive tract involution II. Tissue Cell 2004; 36: 157–169.

    Article  CAS  Google Scholar 

  14. Chen J, Mehta JL, Haider N, Zhang X, Narula J, Li D . Role of caspases in Ox-LDL-induced apoptotic cascade in human coronary artery endothelial cells. Circ Res 2004; 94: 269–270.

    Article  Google Scholar 

  15. Renier G, Maingrette F, Li L . Diabetic vasculopathy and the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). Curr Diabetes Rev 2007; 3: 103–110.

    Article  CAS  Google Scholar 

  16. Dunn S, Vohra RS, Murphy JE, Homer-Vanniasinkam S, Walker JH, Ponnambalam S . The lectin-like oxidized low-density-lipoprotein receptor: a pro-inflammatory factor in vascular disease. Biocheml J 2008; 409: 349–355.

    Article  CAS  Google Scholar 

  17. Nowicki M, Zabirnyk O, Duerrschmidt N, Borlak J, Spanel-Borowski K . No upregulation of lectin-like oxidized low-density lipoprotein receptor-1 in serum-deprived EA. hy926 endothelial cells under oxLDL exposure, but increase in autophagy. Eur J Cell Biol 2007; 86: 605–616.

    Article  CAS  Google Scholar 

  18. Serke H, Vilser C, Nowicki M, Hmeidan FA, Blumenauer V, Hummitzsch K et al. Granulosa cell subtypes respond by autophagy or cell death to oxLDL-dependent activation of the oxidized lipoprotein receptor 1 and toll-like 4 receptor. Autophagy 2009; 5: 991–1003.

    Article  CAS  Google Scholar 

  19. Nowicki M, Müller K, Serke H, Kosacka J, Vilser C, Ricken A et al. Oxidized low-density lipoprotein (oxLDL)-induced cell death in dorsal root ganglion cell cultures depends not on the lectin-like oxLDL receptor-1 but on the toll-like receptor-4. J Neurosci Res 2010; 88: 403–412.

    Article  CAS  Google Scholar 

  20. Olatinwo MO, Bhat GK, Stah CD, Mann DR . Impact of gonadotropin administration on folliculogenesis in prepubertal ob/ob mice. Mol Cell Endocrinol 2005; 245: 121–127.

    Article  CAS  Google Scholar 

  21. Spanel-Borowski K, Schäfer I, Zimmermann S, Engel W, Adham IM . Increase in final stages of follicular atresia and premature decay of corpora lutea in Insl3-deficient mice. Mol Reprod Dev 2001; 58: 281–286.

    Article  CAS  Google Scholar 

  22. Xie Z, Klionsky DJ . Autophagosomes formation: core machinery and adaptations. Nat Cell Biol 2007; 9: 1102–1109.

    Article  CAS  Google Scholar 

  23. Vilser C, Hueller H, Nowicki M, Hmeidan FA, Blumenauer V, Spanel-Borowski K . The variable expression of lectin-like oxidized low-density lipoprotein receptor (LOX-1) and signs of autophagy and apoptosis in freshly harvested human granulosa cells depend on gonadotropin dose, age, and body weight. Fertil Steril 2010; 93: 2706–2715.

    Article  CAS  Google Scholar 

  24. Serke H, Bausenwein J, Hirrlinger J, Nowicki M, Vilser C, Jogschies P et al. Granulosa cell subtypes vary in response to oxidized low-density lipoprotein as regards specific lipoprotein receptors and antioxidant enzyme activity. J Clin Endocrinol Metab 2010; 95: 3480–3490.

    Article  CAS  Google Scholar 

  25. Ilan E, Tirosh O, Mada Z . Triacylglycerol-mediated oxydative stress inhibits nitric oxide production in rat isolated hepatocytes. J Nutr 2005; 135: 2090–2095.

    Article  CAS  Google Scholar 

  26. Santangelo C, Matarrese P, Masella R, Di Carlo MC, Di Lillo A, Scazzocchio B et al. Hepatocyte growth factor protects rat RINm5F cell line against free fatty acid-induced apoptosis by counteracting oxidative stress. J Mol Endocrinol 2007; 38: 147–158.

    Article  CAS  Google Scholar 

  27. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y et al. Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Inves 2004; 114: 1752–1761.

    Article  CAS  Google Scholar 

  28. Clark BJ, Wells J, King SR, Stocco DM . The purification, clonig, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR). J Biol Chem 1994; 269: 28314–28322.

    CAS  PubMed  Google Scholar 

  29. Febbraio M, Hajjar DP, Silverstein RL . CD36: a class B scavenger receptor involved in angiogenesis, atherosclerosis, inflammation, and lipid metabolism. J Clin Invest 2001; 108: 785–791.

    Article  CAS  Google Scholar 

  30. Takeuchi O, Akira S . Pattern recognition receptors and inflammation. Cell 2010; 140: 805–820.

    Article  CAS  Google Scholar 

  31. Turvey SE, Broide DH . Innate immunity. J Allergy Clin Immunol 2010; 125: S24–S32.

    Article  Google Scholar 

  32. Kohchi C, Inagawa H, Nishizawa T, Soma G . ROS and innate immunity. Anticancer Res 2009; 29: 817–821.

    CAS  PubMed  Google Scholar 

  33. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS . TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 2006; 116: 3015–3025.

    Article  CAS  Google Scholar 

  34. Stocco C, Telleria C, Gibori G . The molecular control of corpus luteum formation, function, and regression. Endocr Rev 2007; 28: 117–149.

    Article  CAS  Google Scholar 

  35. Gaytán M, Morales C, Sánchez-Criado JE, Gaytán F . Immunolocalization of beclin 1, a bcl-2-binding, autophagy-related protein, in the human ovary: possible relation to life span of corpus luteum. Cell Tissue Res 2008; 331: 509–517.

    Article  Google Scholar 

  36. Van Wezel IL, Dharmarajan AM, Lavranos TC, Rodgers RJ . Evidence for alternative pathways of granulosa cell death in healthy and slightly atretic bovine antral follicles. Endocrinology 1999; 140: 2602–2612.

    Article  CAS  Google Scholar 

  37. Spanel-Borowski K, Sterzik K . Ultrastructure of human preovulatory granulosa cells in follicular fluid aspirates. Arch Gynecol 1987; 240: 137–146.

    Article  CAS  Google Scholar 

  38. Nottola SA, Heyn R, Camboni A, Correr S, Macchiarelli G . Ultrastructural characteristics of human granulosa cells in a coculture system for in vitro fertilization. Microsc Res Tech 2006; 69: 508–516.

    Article  Google Scholar 

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Acknowledgements

The authors thank Judith Craatz for the technical support in the ultrastructural technique. Financial support was provided by the German Research Foundation (DFG) to Sp232/12-1.

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Author notes

  1. H Serke and M Nowicki: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Anatomy, University of Leipzig, Leipzig, Germany

    H Serke, M Nowicki, T Schröder, S Kallendrusch & K Spanel-Borowski

  2. Department of Internal Medicine III, University of Leipzig, Leipzig, Germany

    J Kosacka, N Klöting & M Blüher

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  1. H Serke
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  2. M Nowicki
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  3. J Kosacka
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Correspondence to H Serke.

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Serke, H., Nowicki, M., Kosacka, J. et al. Leptin-deficient (ob/ob) mouse ovaries show fatty degeneration, enhanced apoptosis and decreased expression of steroidogenic acute regulatory enzyme. Int J Obes 36, 1047–1053 (2012). https://doi.org/10.1038/ijo.2011.220

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