Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2008 (2008), Article ID 243791, 19 pages
http://dx.doi.org/10.1155/2008/243791
Review Article

PPAR Gamma: Coordinating Metabolic and Immune Contributions to Female Fertility

Research Centre for Reproductive Health, School of Paediatrics and Reproductive Health, The University of Adelaide, South Australia 5005, Australia

Received 2 April 2007; Accepted 2 July 2007

Academic Editor: Pascal Froment

Copyright © 2008 Cadence E. Minge 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. Komar and T. E. Curry Jr., “Inverse relationship between the expression of messenger ribonucleic acid for peroxisome proliferator-activated receptor γ and P450 side chain cleavage in the rat ovary,” Biology of Reproduction, vol. 69, no. 2, pp. 549–555, 2003. View at Publisher · View at Google Scholar · View at PubMed
  2. C. E. Minge, N. K. Ryan, K. H. Van Der Hoek, R. L. Robker, and R. J. Norman, “Troglitazone regulates peroxisome proliferator-activated receptors and inducible nitric oxide synthase in murine ovarian macrophages,” Biology of Reproduction, vol. 74, no. 1, pp. 153–160, 2006. View at Publisher · View at Google Scholar · View at PubMed
  3. C. M. Komar, O. Braissant, W. Wahli, and T. E. Curry Jr., “Expression and localization of PPARs in the rat ovary during follicular development and the periovulatory period,” Endocrinology, vol. 142, no. 11, pp. 4831–4838, 2001. View at Publisher · View at Google Scholar
  4. S. Gasic, Y. Bodenburg, M. Nagamani, A. Green, and R. J. Urban, “Troglitazone inhibits progesterone production in porcine granulosa cells,” Endocrinology, vol. 139, no. 12, pp. 4962–4966, 1998. View at Publisher · View at Google Scholar
  5. M. Mohan, J. R. Malayer, R. D. Geisert, and G. L. Morgan, “Expression patterns of retinoid X receptors, retinaldehyde dehydrogenase, and peroxisome proliferator activated receptor γ in bovine preattachment embryos,” Biology of Reproduction, vol. 66, no. 3, pp. 692–700, 2002. View at Publisher · View at Google Scholar
  6. P. Froment, S. Fabre, and J. Dupont et al., “Expression and functional role of peroxisome proliferator-activated receptor-γ in ovarian folliculogenesis in the sheep,” Biology of Reproduction, vol. 69, no. 5, pp. 1665–1674, 2003. View at Publisher · View at Google Scholar · View at PubMed
  7. C. Dreyer and H. Ellinger-Ziegelbauer, “Retinoic acid receptors and nuclear orphan receptors in the development of Xenopus laevis,” International Journal of Developmental Biology, vol. 40, no. 1, pp. 255–262, 1996.
  8. C. M. Komar and T. E. Curry Jr., “Localization and expression of messenger RNAs for the peroxisome proliferator-activated receptors in ovarian tissue from naturally cycling and pseudopregnant rats,” Biology of Reproduction, vol. 66, no. 5, pp. 1531–1539, 2002. View at Publisher · View at Google Scholar
  9. C. M. Komar, “Peroxisome proliferator-activated receptors (PPARs) and ovarian function—implications for regulating steroidogenesis, differentiation, and tissue remodeling,” Reproductive Biology and Endocrinology, vol. 3, no. 41, 2005. View at Publisher · View at Google Scholar · View at PubMed
  10. P. Froment, F. Gizard, D. Defever, B. Staels, J. Dupont, and P. Monget, “Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition,” Journal of Endocrinology, vol. 189, no. 2, pp. 199–209, 2006. View at Publisher · View at Google Scholar · View at PubMed
  11. R. Wu, K. H. Van der Hoek, N. K. Ryan, R. J. Norman, and R. L. Robker, “Macrophage contributions to ovarian function,” Human Reproduction Update, vol. 10, no. 2, pp. 119–133, 2004. View at Publisher · View at Google Scholar · View at PubMed
  12. O. Braissant, F. Foufelle, C. Scotto, M. Dauça, and W. Wahli, “Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat,” Endocrinology, vol. 137, no. 1, pp. 354–366, 1996. View at Publisher · View at Google Scholar
  13. Y. Cui, K. Miyoshi, and E. Claudio et al., “Loss of the peroxisome proliferation-activated receptor γ (PPARγ) does not affect mammary development and propensity for tumor formation but leads to reduced fertility,” Journal of Biological Chemistry, vol. 277, no. 20, pp. 17830–17835, 2002. View at Publisher · View at Google Scholar · View at PubMed
  14. P. D. Schoppee, J. C. Garmey, and J. D. Veldhuis, “Putative activation of the peroxisome proliferator-activated receptor γ impairs androgen and enhances progesterone biosynthesis in primary cultures of porcine theca cells,” Biology of Reproduction, vol. 66, no. 1, pp. 190–198, 2002. View at Publisher · View at Google Scholar
  15. B. Löhrke, T. Viergutz, and S. K. Shahi et al., “Detection and functional characterisation of the transcription factor peroxisome proliferator-activated receptor γ in lutein cells,” Journal of Endocrinology, vol. 159, no. 3, pp. 429–439, 1998. View at Publisher · View at Google Scholar
  16. H. Sundvold, A. Brzozowska, and S. Lien, “Characterisation of bovine peroxisome proliferator-activated receptors γ1 and γ2: genetic mapping and differential expression of the two isoforms,” Biochemical and Biophysical Research Communications, vol. 239, no. 3, pp. 857–861, 1997. View at Publisher · View at Google Scholar · View at PubMed
  17. K. G. Lambe and J. D. Tugwood, “A human peroxisome-proliferator-activated receptor-γ is activated by inducers of adipogenesis, including thiazalidinedione drugs,” European Journal of Biochemistry, vol. 239, no. 1, pp. 1–7, 1996. View at Publisher · View at Google Scholar
  18. Y.-M. Mu, T. Yanase, and Y. Nishi et al., “Insulin sensitizer, troglitazone, directly inhibits aromatase activity in human ovarian granulosa cells,” Biochemical and Biophysical Research Communications, vol. 271, no. 3, pp. 710–713, 2000. View at Publisher · View at Google Scholar · View at PubMed
  19. A. Chawla, E. J. Schwarz, D. D. Dimaculangan, and M. A. Lazar, “Peroxisome proliferator-activated receptor (PPAR) γ: adipose-predominant expression and induction early in adipocyte differentiation,” Endocrinology, vol. 135, no. 2, pp. 798–800, 1994. View at Publisher · View at Google Scholar
  20. A. Chawla, Y. Barak, L. Nagy, D. Liao, P. Tontonoz, and R. M. Evans, “PPAR-γ dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation,” Nature Medicine, vol. 7, no. 1, pp. 48–52, 2001. View at Publisher · View at Google Scholar · View at PubMed
  21. P. Tontonoz, E. Hu, and B. M. Spiegelman, “Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor,” Cell, vol. 79, no. 7, pp. 1147–1156, 1994. View at Publisher · View at Google Scholar
  22. E. D. Rosen, P. Sarraf, and A. E. Troy et al., “PPARγ is required for the differentiation of adipose tissue in vivo and in vitro,” Molecular Cell, vol. 4, no. 4, pp. 611–617, 1999. View at Publisher · View at Google Scholar
  23. Y. Barak, M. C. Nelson, and E. S. Ong et al., “PPARγ is required for placental, cardiac, and adipose tissue development,” Molecular Cell, vol. 4, no. 4, pp. 585–595, 1999. View at Publisher · View at Google Scholar
  24. M. J. Davies, “Evidence for effects of weight on reproduction in women,” Reproductive BioMedicine Online, vol. 12, no. 5, pp. 552–561, 2006.
  25. R. J. Norman and A. M. Clark, “Obesity and reproductive disorders: a review,” Reproduction, Fertility and Development, vol. 10, no. 1, pp. 55–63, 1998. View at Publisher · View at Google Scholar
  26. Y.-M. Mu, T. Yanase, and Y. Nishi et al., “Saturated FFAs, palmitic acid and stearic acid, induce apoptosis in human granulosa cells,” Endocrinology, vol. 142, no. 8, pp. 3590–3597, 2001. View at Publisher · View at Google Scholar
  27. R. Jorritsma, M. L. César, J. T. Hermans, C. L. J. J. Kruitwagen, P. L. A. M. Vos, and T. A. M. Kruip, “Effects of non-esterified fatty acids on bovine granulosa cells and developmental potential of oocytes in vitro,” Animal Reproduction Science, vol. 81, no. 3-4, pp. 225–235, 2004. View at Publisher · View at Google Scholar · View at PubMed
  28. T. Vanholder, J. L. M. R. Leroy, and A. Van Soom et al., “Effect of non-esterified fatty acids on bovine granulosa cell steroidogenesis and proliferation in vitro,” Animal Reproduction Science, vol. 87, no. 1-2, pp. 33–44, 2005. View at Publisher · View at Google Scholar · View at PubMed
  29. M. Mitchell, D. T. Armstrong, R. L. Robker, and R. J. Norman, “Adipokines: implications for female fertility and obesity,” Reproduction, vol. 130, no. 5, pp. 583–597, 2005. View at Publisher · View at Google Scholar · View at PubMed
  30. A. M. Bodles, V. Varma, and A. Yao-Borengasser et al., “Pioglitazone induces apoptosis of macrophages in human adipose tissue,” Journal of Lipid Research, vol. 47, no. 9, pp. 2080–2088, 2006. View at Publisher · View at Google Scholar · View at PubMed
  31. L. Fajas, J.-C. Fruchart, and J. Auwerx, “PPARγ3 mRNA: a distinct PPARγ mRNA subtype transcribed from an independent promoter,” FEBS Letters, vol. 438, no. 1-2, pp. 55–60, 1998. View at Publisher · View at Google Scholar
  32. P. Tontonoz, R. A. Graves, and A. I. Budavari et al., “Adipocyte-specific transcription factor ARF6 is a heterodimeric complex of two nuclear hormone receptors, PPAR γ and RXR α,” Nucleic Acids Research, vol. 22, no. 25, pp. 5628–5634, 1994. View at Publisher · View at Google Scholar
  33. H. Sundvold and S. Lien, “Identification of a novel peroxisome proliferator-activated receptor (PPAR) γ promoter in man and transactivation by the nuclear receptor RORα1,” Biochemical and Biophysical Research Communications, vol. 287, no. 2, pp. 383–390, 2001. View at Publisher · View at Google Scholar · View at PubMed
  34. B. Desvergne and W. Wahli, “Peroxisome proliferator-activated receptors: nuclear control of metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999. View at Publisher · View at Google Scholar
  35. R. Mukherjee, L. Jow, G. E. Croston, and J. R. Paterniti Jr., “Identification, characterization, and tissue distribution of human peroxisome proliferator-activated receptor (PPAR) isoforms PPARγ2 versus PPARγ1 and activation with retinoid X receptor agonists and antagonists,” Journal of Biological Chemistry, vol. 272, no. 12, pp. 8071–8076, 1997. View at Publisher · View at Google Scholar
  36. L. Fajas, D. Auboeuf, and E. Raspé et al., “The organization, promoter analysis, and expression of the human PPARγ gene,” Journal of Biological Chemistry, vol. 272, no. 30, pp. 18779–18789, 1997. View at Publisher · View at Google Scholar
  37. T. E. Akiyama, S. Sakai, and G. Lambert et al., “Conditional disruption of the peroxisome proliferator-activated receptor γ gene in mice results in lowered expression of ABCA1, ABCG1, and apoE in macrophages and reduced cholesterol efflux,” Molecular and Cellular Biology, vol. 22, no. 8, pp. 2607–2619, 2002. View at Publisher · View at Google Scholar
  38. H. Koutnikova, T.-A. Cock, and M. Watanabe et al., “Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPARγ hypomorphic mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 24, pp. 14457–14462, 2003. View at Publisher · View at Google Scholar · View at PubMed
  39. D. Altshuler, J. N. Hirschhorn, and M. Klannemark et al., “The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes,” Nature Genetics, vol. 26, no. 1, pp. 76–80, 2000. View at Publisher · View at Google Scholar · View at PubMed
  40. S. S. Deeb, L. Fajas, and M. Nemoto et al., “A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity,” Nature Genetics, vol. 20, no. 3, pp. 284–287, 1998. View at Publisher · View at Google Scholar · View at PubMed
  41. M. M. Swarbrick, C. M. L. Chapman, B. M. McQuillan, J. Hung, P. L. Thompson, and J. P. Beilby, “A Pro12Ala polymorphism in the human peroxisome proliferator-activated receptor-γ2 is associated with combined hyperlipidaemia in obesity,” European Journal of Endocrinology, vol. 144, no. 3, pp. 277–282, 2001. View at Publisher · View at Google Scholar
  42. B. A. Beamer, C.-J. Yen, and R. E. Andersen et al., “Association of the Pro12Ala variant in the peroxisome proliferator- activated receptor-γ2 gene with obesity in two Caucasian populations,” Diabetes, vol. 47, no. 11, pp. 1806–1808, 1998. View at Publisher · View at Google Scholar
  43. E. C. Tok, A. Aktas, D. Ertunc, E. M. Erdal, and S. Dilek, “Evaluation of glucose metabolism and reproductive hormones in polycystic ovary syndrome on the basis of peroxisome proliferator-activated receptor (PPAR)-γ2 Pro12Ala genotype,” Human Reproduction, vol. 20, no. 6, pp. 1590–1595, 2005. View at Publisher · View at Google Scholar · View at PubMed
  44. A. Meirhaeghe, L. Fajas, and N. Helbecque et al., “A genetic polymorphism of the peroxisome proliferator-activated receptor γ gene influences plasma leptin levels in obese humans,” Human Molecular Genetics, vol. 7, no. 3, pp. 435–440, 1998. View at Publisher · View at Google Scholar
  45. F. Orio Jr., G. Matarese, and S. Di Biase et al., “Exon 6 and 2 peroxisome proliferator-activated receptor-γ polymorphisms in polycystic ovary syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 12, pp. 5887–5892, 2003. View at Publisher · View at Google Scholar
  46. A. Doney, B. Fischer, and D. Frew et al., “Haplotype analysis of the PPARγ Pro12Ala and C1431T variants reveals opposing associations with body weight,” BMC Genetics, vol. 3, no. 1, p. 21, 2002. View at Publisher · View at Google Scholar
  47. J. Ek, G. Andersen, and S. A. Urhammer et al., “Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) gene in relation to insulin sensitivity among glucose tolerant caucasians,” Diabetologia, vol. 44, no. 9, pp. 1170–1176, 2001. View at Publisher · View at Google Scholar
  48. C. Vigouroux, L. Fajas, and E. Khallouf et al., “Human peroxisome proliferator-activated receptor-γ2: genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipoatrophic diabetes,” Diabetes, vol. 47, no. 3, pp. 490–492, 1998. View at Publisher · View at Google Scholar
  49. J. Pihlajamäki, R. Miettinen, and R. Valve et al., “The Pro12Ala substitution in the peroxisome proliferator activated receptor γ 2 is associated with an insulin-sensitive phenotype in families with familial combined hyperlipidemia and in nondiabetic elderly subjects with dyslipidemia,” Atherosclerosis, vol. 151, no. 2, pp. 567–574, 2000. View at Publisher · View at Google Scholar
  50. A. Hamann, H. Münzberg, and P. Buttron et al., “Missense variants in the human peroxisome proliferator-activated receptor-γ2 gene in lean and obese subjects,” European Journal of Endocrinology, vol. 141, no. 1, pp. 90–92, 1999. View at Publisher · View at Google Scholar
  51. J. Ringel, S. Engeli, A. Distler, and A. M. Sharma, “Pro12Ala missense mutation of the peroxisome proliferator activated receptor γ and diabetes mellitus,” Biochemical and Biophysical Research Communications, vol. 254, no. 2, pp. 450–453, 1999. View at Publisher · View at Google Scholar · View at PubMed
  52. Y. Mori, H. Kim-Motoyama, and T. Katakura et al., “Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor γ2 gene on adiposity, fat distribution, and insulin sensitivity in Japanese men,” Biochemical and Biophysical Research Communications, vol. 251, no. 1, pp. 195–198, 1998. View at Publisher · View at Google Scholar · View at PubMed
  53. M. Koch, K. Rett, and E. Maerker et al., “The PPARγ2 amino acid polymorphism Pro12Ala is prevalent in offspring of type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects,” Diabetologia, vol. 42, no. 6, pp. 758–762, 1999. View at Publisher · View at Google Scholar
  54. K. Hara, T. Okada, and K. Tobe et al., “The Pro12Ala polymorphism in PPAR γ2 may confer resistance to type 2 diabetes,” Biochemical and Biophysical Research Communications, vol. 271, no. 1, pp. 212–216, 2000. View at Publisher · View at Google Scholar · View at PubMed
  55. M. Yilmaz, M. Ali Ergün, A. Karakoç, E. Yurtçu, N. Çakir, and M. Arslan, “Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ gene in women with polycystic ovary syndrome,” Gynecological Endocrinology, vol. 22, no. 6, pp. 336–342, 2006. View at Publisher · View at Google Scholar · View at PubMed
  56. S. Hahn, A. Fingerhut, and U. Khomtsiv et al., “The peroxisome proliferator activated receptor γ Pro12Ala polymorphism is associated with a lower hirsutism score and increased insulin sensitivity in women with polycystic ovary syndrome,” Clinical Endocrinology, vol. 62, no. 5, pp. 573–579, 2005. View at Publisher · View at Google Scholar · View at PubMed
  57. S. Korhonen, S. Heinonen, and M. Hiltunen et al., “Polymorphism in the peroxisome proliferator-activated receptor-γ gene in women with polycystic ovary syndrome,” Human Reproduction, vol. 18, no. 3, pp. 540–543, 2003. View at Publisher · View at Google Scholar
  58. M. Ristow, D. Müller-Wieland, A. Pfeiffer, W. Krone, and C. R. Kahn, “Obesity associated with a mutation in a genetic regulator of adipocyte differentiation,” New England Journal of Medicine, vol. 339, no. 14, pp. 953–959, 1998. View at Publisher · View at Google Scholar
  59. I. Barroso, M. Gurnell, and V. E. F. Crowley et al., “Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension,” Nature, vol. 402, no. 6764, pp. 880–883, 1999. View at Publisher · View at Google Scholar · View at PubMed
  60. D. B. Savage, G. D. Tan, and C. L. Acerini et al., “Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-γ,” Diabetes, vol. 52, no. 4, pp. 910–917, 2003. View at Publisher · View at Google Scholar
  61. R. A. Hegele, H. Cao, C. Frankowski, S. T. Mathews, and T. Leff, “PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy,” Diabetes, vol. 51, no. 12, pp. 3586–3590, 2002. View at Publisher · View at Google Scholar
  62. A. K. Agarwal and A. Garg, “A novel heterozygous mutation in peroxisome proliferator-activated receptor-γ gene in a patient with familial partial lipodystrophy,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 1, pp. 408–411, 2002. View at Publisher · View at Google Scholar
  63. H. E. Xu, M. H. Lambert, and V. G. Montana et al., “Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 24, pp. 13919–13924, 2001. View at Publisher · View at Google Scholar · View at PubMed
  64. J. Berger and D. E. Moller, “The mechanisms of action of PPARs,” Annual Review of Medicine, vol. 53, pp. 409–435, 2002. View at Publisher · View at Google Scholar · View at PubMed
  65. A. Tsafriri, “Ovulation as a tissue remodelling process: proteolysis and cumulus expansion,” Advances in Experimental Medicine and Biology, vol. 377, pp. 121–140, 1995.
  66. B. Dennefors, L. Hamberger, and T. Hillensjo, “Aspects concerning the role of prostaglandins for ovarian function,” Acta Obstetricia et Gynecologica Scandinavica, vol. 113, supplement, pp. 31–41, 1983.
  67. G. Evans, M. Dobias, G. J. King, and D. T. Armstrong, “Production of prostaglandins by porcine preovulatory follicular tissues and their roles in intrafollicular function,” Biology of Reproduction, vol. 28, no. 2, pp. 322–328, 1983. View at Publisher · View at Google Scholar
  68. D. T. Armstrong, “Prostaglandins and follicular functions,” Journal of Reproduction and Fertility, vol. 62, no. 1, pp. 283–291, 1981.
  69. A. V. Pontsler, A. St Hilaire, G. K. Marathe, G. A. Zimmerman, and T. M. McIntyre, “Cyclooxygenase-2 is induced in monocytes by peroxisome proliferator activated receptor γ and oxidized alkyl phospholipids from oxidized low density lipoprotein,” Journal of Biological Chemistry, vol. 277, no. 15, pp. 13029–13036, 2002. View at Publisher · View at Google Scholar · View at PubMed
  70. M. F. M. Mitwally, N. K. Kuscu, and T. M. Yalcinkaya, “High ovulatory rates with use of troglitazone in clomiphene-resistant women with polycystic ovary syndrome,” Human Reproduction, vol. 14, no. 11, pp. 2700–2703, 1999. View at Publisher · View at Google Scholar
  71. I. Hasegawa, H. Murakawa, M. Suzuki, Y. Yamamoto, T. Kurabayashi, and K. Tanaka, “Effect of troglitazone on endocrine and ovulatory performance in women with insulin resistance-related polycystic ovary syndrome,” Fertility and Sterility, vol. 71, no. 2, pp. 323–327, 1999. View at Publisher · View at Google Scholar
  72. D. A. Ehrmann, D. J. Schneider, and B. E. Sobel et al., “Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 7, pp. 2108–2116, 1997. View at Publisher · View at Google Scholar
  73. R. Azziz, D. Ehrmann, and R. S. Legro et al., “Troglitazone improves ovulation and hirsutism in the polycystic ovary syndrome: a multicenter, double blind, placebo-controlled trial,” Journal of Clinical Endocrinology and Metabolism, vol. 86, no. 4, pp. 1626–1632, 2001. View at Publisher · View at Google Scholar
  74. F. Picard and J. Auwerx, “PPARγ and glucose homeostasis,” Annual Review of Nutrition, vol. 22, pp. 167–197, 2002. View at Publisher · View at Google Scholar · View at PubMed
  75. A. A. Rouzi and M. S. M. Ardawi, “A randomized controlled trial of the efficacy of rosiglitazone and clomiphene citrate versus metformin and clomiphene citrate in women with clomiphene citrate-resistant polycystic ovary syndrome,” Fertility and Sterility, vol. 85, no. 2, pp. 428–435, 2006. View at Publisher · View at Google Scholar · View at PubMed
  76. C. Ortega-González, S. Luna, and L. Hernández et al., “Responses of serum androgen and insulin resistance to metformin and pioglitazone in obese, insulin-resistant women with polycystic ovary syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 3, pp. 1360–1365, 2005. View at Publisher · View at Google Scholar · View at PubMed
  77. N. Brettenthaler, C. De Geyter, P. R. Huber, and U. Keller, “Effect of the insulin sensitizer pioglitazone on insulin resistance, hyperandrogenism, and ovulatory dysfunction in women with polycystic ovary syndrome,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 8, pp. 3835–3840, 2004. View at Publisher · View at Google Scholar · View at PubMed
  78. S. H. Belli, M. N. Graffigna, A. Oneto, P. Otero, L. Schurman, and O. A. Levalle, “Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome,” Fertility and Sterility, vol. 81, no. 3, pp. 624–629, 2004. View at Publisher · View at Google Scholar · View at PubMed
  79. A. Shobokshi and M. Shaarawy, “Correction of insulin resistance and hyperandrogenism in polycystic ovary syndrome by combined rosiglitazone and clomiphene citrate therapy,” Journal of the Society for Gynecologic Investigation, vol. 10, no. 2, pp. 99–104, 2003. View at Publisher · View at Google Scholar
  80. D. Seto-Young, M. Paliou, and J. Schlosser et al., “Direct thiazolidinedione action in the human ovary: insulin-independent and insulin-sensitizing effects on steroidogenesis and insulin-like growth factor binding protein-1 production,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 11, pp. 6099–6105, 2005. View at Publisher · View at Google Scholar · View at PubMed
  81. S. Gasic, M. Nagamani, A. Green, and R. J. Urban, “Troglitazone is a competitive inhibitor of 3β-hydroxysteroid dehydrogenase enzyme in the ovary,” American Journal of Obstetrics and Gynecology, vol. 184, no. 4, pp. 575–579, 2001. View at Publisher · View at Google Scholar · View at PubMed
  82. M. S. Coffler, K. Patel, M. H. Dahan, R. Y. Yoo, P. J. Malcom, and R. J. Chang, “Enhanced granulosa cell responsiveness to follicle-stimulating hormone during insulin infusion in women with polycystic ovary syndrome treated with pioglitazone,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 12, pp. 5624–5631, 2003. View at Publisher · View at Google Scholar
  83. C. E. Minge, B. D. Bennett, M. Lane, R. J. Norman, and R. L. Robker, “Obesity-induced female infertility arises from impaired oocyte developmental competence and can be reversed by peri-ovulatory rosiglitazone treatment,” in Proceedings of the 10th International Congress on Obesity, Sydney, Australia, 2006.
  84. W. L. Miller, “Steroidogenic acute regulatory protein (StAR), a novel mitochondrial cholesterol transporter,” Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids, vol. 1771, no. 6, pp. 663–676, 2007. View at Publisher · View at Google Scholar · View at PubMed
  85. D. Seto-Young, D. Avtanski, and M. Strizhevsky et al., “Interactions among peroxisome proliferator activated receptor-γ, insulin signaling pathways, and steroidogenic acute regulatory protein in human ovarian cells,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 6, pp. 2232–2239, 2007. View at Publisher · View at Google Scholar · View at PubMed
  86. W. C. Duncan, G. M. Cowen, and P. J. Illingworth, “Steroidogenic enzyme expression in human corpora lutea in the presence and absence of exogenous human chorionic gonadotrophin (HCG),” Molecular Human Reproduction, vol. 5, no. 4, pp. 291–298, 1999. View at Publisher · View at Google Scholar
  87. K. J. Doody, M. C. Lorence, J. I. Mason, and E. R. Simpson, “Expression of messenger ribonucleic acid species encoding steroidogenic enzymes in human follicles and corpora lutea throughout the menstrual cycle,” Journal of Clinical Endocrinology and Metabolism, vol. 70, no. 4, pp. 1041–1045, 1990.
  88. W. Arlt, R. J. Auchus, and W. L. Miller, “Thiazolidinediones but not metformin directly inhibit the steroidogenic enzymes P450c17 and 3β-hydroxysteroid dehydrogenase,” Journal of Biological Chemistry, vol. 276, no. 20, pp. 16767–16771, 2001. View at Publisher · View at Google Scholar · View at PubMed
  89. P. Kempná, G. Hofer, P. E. Mullis, and C. E. Flück, “Pioglitazone inhibits androgen production in NCI-H295R cells by regulating gene expression of CYP17 and HSD3B2,” Molecular Pharmacology, vol. 71, no. 3, pp. 787–798, 2007. View at Publisher · View at Google Scholar · View at PubMed
  90. J. D. Veldhuis, G. Zhang, and J. C. Garmey, “Troglitazone, an insulin-sensitizing thiazolidinedione, represses combined stimulation by LH and insulin of de novo androgen biosynthesis by thecal cells in vitro,” Journal of Clinical Endocrinology and Metabolism, vol. 87, no. 3, pp. 1129–1133, 2002. View at Publisher · View at Google Scholar
  91. M. P. Steinkampf, C. R. Mendelson, and E. R. Simpson, “Regulation by follicle-stimulating hormone of the synthesis of aromatase cytochrome P-450 in human granulosa cells,” Molecular Endocrinology, vol. 1, no. 7, pp. 465–471, 1987. View at Publisher · View at Google Scholar
  92. J. S. Krasnow, G. J. Hickey, and J. S. Richards, “Regulation of aromatase mRNA and estradiol biosynthesis in rat ovarian granulosa and luteal cells by prolactin,” Molecular Endocrinology, vol. 4, no. 1, pp. 13–21, 1990. View at Publisher · View at Google Scholar
  93. T. Yanase, Y.-M. Mu, and Y. Nishi et al., “Regulation of aromatase by nuclear receptors,” Journal of Steroid Biochemistry and Molecular Biology, vol. 79, no. 1–5, pp. 187–192, 2001. View at Publisher · View at Google Scholar
  94. Y.-M. Mu, T. Yanase, Y. Nishi, R. Takayanagi, K. Goto, and H. Nawata, “Combined treatment with specific ligands for PPARγ:RXR nuclear receptor system markedly inhibits the expression of cytochrome P450arom in human granulosa cancer cells,” Molecular and Cellular Endocrinology, vol. 181, no. 1–2, pp. 239–248, 2001. View at Publisher · View at Google Scholar
  95. W. Fan, T. Yanase, and H. Morinaga et al., “Activation of peroxisome proliferator-activated receptor-γ and retinoid X receptor inhibits aromatase transcription via nuclear factor-κB,” Endocrinology, vol. 146, no. 1, pp. 85–92, 2005. View at Publisher · View at Google Scholar · View at PubMed
  96. K. Rautio, J. S. Tapanainen, A. Ruokonen, and L. C. Morin-Papunen, “Endocrine and metabolic effects of rosiglitazone in overweight women with PCOS: a randomized placebo-controlled study,” Human Reproduction, vol. 21, no. 6, pp. 1400–1407, 2006. View at Publisher · View at Google Scholar · View at PubMed
  97. H. M. Garmes, M. A. Tambascia, and D. E. Zantut-Wittmann, “Endocrine-metabolic effects of the treatment with pioglitazone in obese patients with polycystic ovary syndrome,” Gynecological Endocrinology, vol. 21, no. 6, pp. 317–323, 2005. View at Publisher · View at Google Scholar · View at PubMed
  98. M. Yilmaz, A. Biri, and A. Karakoç et al., “The effects of rosiglitazone and metformin on insulin resistance and serum androgen levels in obese and lean patients with polycystic ovary syndrome,” Journal of Endocrinological Investigation, vol. 28, no. 11, pp. 1003–1008, 2005.
  99. M. Yilmaz, N. Bukan, and G. Ayvaz et al., “The effects of rosiglitazone and metformin on oxidative stress and homocysteine levels in lean patients with polycystic ovary syndrome,” Human Reproduction, vol. 20, no. 12, pp. 3333–3340, 2005. View at Publisher · View at Google Scholar · View at PubMed
  100. M. Yilmaz, A. Karakoç, and F. B. Törüner et al., “The effects of rosiglitazone and metformin on menstrual cyclicity and hirsutism in polycystic ovary syndrome,” Gynecological Endocrinology, vol. 21, no. 3, pp. 154–160, 2005. View at Publisher · View at Google Scholar · View at PubMed
  101. D. Dereli, T. Dereli, F. Bayraktar, A. G. Ozgen, and C. Yilmaz, “Endocrine and metabolic effects of rosiglitazone in non-obese women with polycystic ovary disease,” Endocrine Journal, vol. 52, no. 3, pp. 299–308, 2005. View at Publisher · View at Google Scholar
  102. V. Sepilian and M. Nagamani, “Effects of rosiglitazone in obese women with polycystic ovary syndrome and severe insulin resistance,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 1, pp. 60–65, 2005. View at Publisher · View at Google Scholar · View at PubMed
  103. J.-P. Baillargeon, D. J. Jakubowicz, M. J. Iuorno, S. Jakubowicz, and J. E. Nestler, “Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity,” Fertility and Sterility, vol. 82, no. 4, pp. 893–902, 2004. View at Publisher · View at Google Scholar · View at PubMed
  104. D. Romualdi, M. Guido, and M. Ciampelli et al., “Selective effects of pioglitazone on insulin and androgen abnormalities in normo- and hyperinsulinaemic obese patients with polycystic ovary syndrome,” Human Reproduction, vol. 18, no. 6, pp. 1210–1218, 2003. View at Publisher · View at Google Scholar
  105. T. Lovekamp-Swan, A. M. Jetten, and B. J. Davis, “Dual activation of PPARα and PPARγ by mono-(2-ethylhexyl) phthalate in rat ovarian granulosa cells,” Molecular and Cellular Endocrinology, vol. 201, no. 1–2, pp. 133–141, 2003. View at Publisher · View at Google Scholar
  106. A. Rubenstrunk, R. Hanf, D. W. Hum, J.-C. Fruchart, and B. Staels, “Safety issues and prospects for future generations of PPAR modulators,” Biochimica et Biophysica Acta—Molecular and Cell Biology of Lipids, vol. 1771, no. 8, pp. 1065–1081, 2007. View at Publisher · View at Google Scholar · View at PubMed
  107. A. V. Schwartz, D. E. Sellmeyer, and E. Vittinghoff et al., “Thiazolidinedione use and bone loss in older diabetic adults,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 9, pp. 3349–3354, 2006. View at Publisher · View at Google Scholar · View at PubMed
  108. D. B. Klinkner, H. J. Lim, E. Y. Strawn Jr., K. T. Oldham, and T. L. Sander, “An in vivo murine model of rosiglitazone use in pregnancy,” Fertility and Sterility, vol. 86, no. 4, pp. 1074–1079, 2006. View at Publisher · View at Google Scholar · View at PubMed
  109. N. A. Cataldo, F. Abbasi, T. L. McLaughlin, C. Lamendola, and G. M. Reaven, “Improvement in insulin sensitivity followed by ovulation and pregnancy in a woman with polycystic ovary syndrome who was treated with rosiglitazone,” Fertility and Sterility, vol. 76, no. 5, pp. 1057–1059, 2001. View at Publisher · View at Google Scholar
  110. L. Y.-S. Chan, J. H.-K. Yeung, and T. K. Lau, “Placental transfer of rosiglitazone in the first trimester of human pregnancy,” Fertility and Sterility, vol. 83, no. 4, pp. 955–958, 2005. View at Publisher · View at Google Scholar · View at PubMed
  111. A. Dunaif, “Insulin action in the polycystic ovary syndrome,” Endocrinology and Metabolism Clinics of North America, vol. 28, no. 2, pp. 341–359, 1999. View at Publisher · View at Google Scholar
  112. L. Poretsky, J. Clemons, and K. Bogovich, “Hyperinsulinemia and human chorionic gonadotropin synergistically promote the growth of ovarian follicular cysts in rats,” Metabolism, vol. 41, no. 8, pp. 903–910, 1992. View at Publisher · View at Google Scholar
  113. N. K. Kuşcu, F. Koyuncu, K. Özbilgin, S. Inan, I. Tuğlu, and Ö. Karaer, “Insulin: does it induce follicular arrest in the rat ovary?,” Gynecological Endocrinology, vol. 16, no. 5, pp. 361–364, 2002.
  114. S. Hashimoto, N. Minami, M. Yamada, and H. Imai, “Excessive concentration of glucose during in vitro maturation impairs the developmental competence of bovine oocytes after in vitro fertilization: relevance to intracellular reactive oxygen species and glutathione contents,” Molecular Reproduction and Development, vol. 56, no. 4, pp. 520–526, 2000. View at Publisher · View at Google Scholar
  115. S. A. Colton, G. M. Pieper, and S. M. Downs, “Altered meiotic regulation in oocytes from diabetic mice,” Biology of Reproduction, vol. 67, no. 1, pp. 220–231, 2002. View at Publisher · View at Google Scholar
  116. J. Rieusset, J. Auwerx, and H. Vidal, “Regulation of gene expression by activation of the peroxisome proliferator-activated receptor γ with rosiglitazone (BRL 49653) in human adipocytes,” Biochemical and Biophysical Research Communications, vol. 265, no. 1, pp. 265–271, 1999. View at Publisher · View at Google Scholar · View at PubMed
  117. U. Smith, S. Gogg, A. Johansson, T. Olausson, V. Rotter, and B. Svalstedt, “Thiazolidinediones (PPARγ agonists) but not PPARα agonists increase IRS-2 gene expression in 3T3-L1 and human adipocytes,” FASEB Journal, vol. 15, no. 1, pp. 215–220, 2001. View at Publisher · View at Google Scholar · View at PubMed
  118. T. P. Ciaraldi, A. P. S. Kong, and N. V. Chu et al., “Regulation of glucose transport and insulin signaling by troglitazone or metformin in adipose tissue of type 2 diabetic subjects,” Diabetes, vol. 51, no. 1, pp. 30–36, 2002. View at Publisher · View at Google Scholar
  119. L. M. Furtado, V. Poon, and A. Klip, “GLUT4 activation: thoughts on possible mechanisms,” Acta Physiologica Scandinavica, vol. 178, no. 4, pp. 287–296, 2003. View at Publisher · View at Google Scholar
  120. N. Khandoudi, P. Delerive, I. Berrebi-Bertrand, R. E. Buckingham, B. Staels, and A. Bril, “Rosiglitazone, a peroxisome proliferator-activated receptor-γ, inhibits the Jun NH2-terminal kinase/activating protein 1 pathway and protects the heart from ischemia/reperfusion injury,” Diabetes, vol. 51, no. 5, pp. 1507–1514, 2002. View at Publisher · View at Google Scholar
  121. G. Jiang, Q. Dallas-Yang, S. Biswas, Z. Li, and B. B. Zhang, “Rosiglitazone, an agonist of peroxisome-proliferator-activated receptor γ (PPARγ), decreases inhibitory serine phosphorylation of IRS1 in vitro and in vivo,” Biochemical Journal, vol. 377, no. 2, pp. 339–346, 2004. View at Publisher · View at Google Scholar · View at PubMed
  122. G. Jiang and B. B. Zhang, “Modulation of insulin signalling by insulin sensitizers,” Biochemical Society Transactions, vol. 33, no. 2, pp. 358–361, 2005. View at Publisher · View at Google Scholar · View at PubMed
  123. L. Guo and R. Tabrizchi, “Peroxisome proliferator-activated receptor gamma as a drug target in the pathogenesis of insulin resistance,” Pharmacology and Therapeutics, vol. 111, no. 1, pp. 145–173, 2006. View at Publisher · View at Google Scholar · View at PubMed
  124. S.-Y. Ku, S. D. Kim, and B. C. Jee et al., “Clinical efficacy of body mass index as predictor of in vitro fertilization and embryo transfer outcomes,” Journal of Korean Medical Science, vol. 21, no. 2, pp. 300–303, 2006.
  125. A. Bongain, V. Isnard, and J.-Y. Gillet, “Obesity in obstetrics and gynaecology,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 77, no. 2, pp. 217–228, 1998. View at Publisher · View at Google Scholar
  126. Y. Linné, “Effects of obesity on women's reproduction and complications during pregnancy,” Obesity Reviews, vol. 5, no. 3, pp. 137–143, 2004.
  127. G. A. Bray, “Obesity and reproduction,” Human Reproduction, vol. 12, no. 1, pp. 26–32, 1997.
  128. J. X. Wang, M. Davies, and R. J. Norman, “Body mass and probability of pregnancy during assisted reproduction treatment: retrospective study,” British Medical Journal, vol. 321, no. 7272, pp. 1320–1321, 2000. View at Publisher · View at Google Scholar
  129. R. Pasquali, C. Pelusi, S. Genghini, M. Cacciari, and A. Gambineri, “Obesity and reproductive disorders in women,” Human Reproduction Update, vol. 9, no. 4, pp. 359–372, 2003. View at Publisher · View at Google Scholar
  130. B. M. Zaadstra, J. C. Seidell, and P. A. H. Van Noord et al., “Fat and female fecundity: prospective study of effect of body fat distribution on conception rates,” British Medical Journal, vol. 306, no. 6876, pp. 484–487, 1993. View at Publisher · View at Google Scholar
  131. A. Fukuhara, M. Matsuda, and M. Nishizawa et al., “Visfatin: a protein secreted by visceral fat that mimics the effects of insulin,” Science, vol. 307, no. 5708, pp. 426–430, 2005. View at Publisher · View at Google Scholar · View at PubMed
  132. T. E. Graham, Q. Yang, and M. Blüher et al., “Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects,” New England Journal of Medicine, vol. 354, no. 24, pp. 2552–2563, 2006. View at Publisher · View at Google Scholar · View at PubMed
  133. B. K. Tan, J. Chen, J. E. Digby, S. D. Keay, C. R. Kennedy, and H. S. Randeva, “Increased visfatin messenger ribonucleic acid and protein levels in adipose tissue and adipocytes in women with polycystic ovary syndrome: parallel increase in plasma visfatin,” Journal of Clinical Endocrinology and Metabolism, vol. 91, no. 12, pp. 5022–5028, 2006. View at Publisher · View at Google Scholar · View at PubMed
  134. B. K. Tan, J. Chen, H. Lehnert, R. Kennedy, and H. S. Randeva, “Raised serum, adipocyte, and adipose tissue retinol-binding protein 4 in overweight women with polycystic ovary syndrome: effects of gonadal and adrenal steroids,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 7, pp. 2764–2772, 2007. View at Publisher · View at Google Scholar · View at PubMed
  135. M. Iwaki, M. Matsuda, and N. Maeda et al., “Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors,” Diabetes, vol. 52, no. 7, pp. 1655–1663, 2003. View at Publisher · View at Google Scholar
  136. P. De Vos, A.-M. Lefebvre, and S. G. Miller et al., “Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor γ,” Journal of Clinical Investigation, vol. 98, no. 4, pp. 1004–1009, 1996. View at Publisher · View at Google Scholar
  137. D. Sinha, S. Addya, E. Murer, and G. Boden, “15-Deoxy-Δ12,14 prostaglandin J2: a putative endogenous promoter of adipogenesis suppresses the ob gene,” Metabolism, vol. 48, no. 6, pp. 786–791, 1999. View at Publisher · View at Google Scholar
  138. C. B. Kallen and M. A. Lazar, “Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3-L1 adipocytes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 12, pp. 5793–5796, 1996. View at Publisher · View at Google Scholar
  139. Y. Miyazaki, A. Mahankali, E. Wajcberg, M. Bajaj, L. J. Mandarino, and R. A. DeFronzo, “Effect of pioglitazone on circulating adipocytokine levels and insulin sensitivity in type 2 diabetic patients,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 9, pp. 4312–4319, 2004. View at Publisher · View at Google Scholar · View at PubMed
  140. C. Otto, B. Otto, and B. Göke et al., “Increase in adiponectin levels during pioglitazone therapy in relation to glucose control, insulin resistance as well as ghrelin and resistin levels,” Journal of Endocrinological Investigation, vol. 29, no. 3, pp. 231–236, 2006.
  141. L. J. Spicer and C. C. Francisco, “The adipose obese gene product, leptin: evidence of a direct inhibitory role in ovarian function,” Endocrinology, vol. 138, no. 8, pp. 3374–3379, 1997. View at Publisher · View at Google Scholar
  142. C. Karlsson, K. Lindell, and E. Svensson et al., “Expression of functional leptin receptors in the human ovary,” Journal of Clinical Endocrinology and Metabolism, vol. 82, no. 12, pp. 4144–4148, 1997. View at Publisher · View at Google Scholar
  143. N. K. Ryan, K. H. Van der Hoek, S. A. Robertson, and R. J. Norman, “Leptin and leptin receptor expression in the rat ovary,” Endocrinology, vol. 144, no. 11, pp. 5006–5013, 2003. View at Publisher · View at Google Scholar · View at PubMed
  144. R. J. Zachow and D. A. Magoffin, “Direct intraovarian effects of leptin: impairment of the synergistic action of insulin-like growth factor-I on follicle-stimulating hormone- dependent estradiol-17β production by rat ovarian granulosa cells,” Endocrinology, vol. 138, no. 2, pp. 847–850, 1997. View at Publisher · View at Google Scholar
  145. N. K. Ryan, C. M. Woodhouse, K. H. Van der Hoek, R. B. Gilchrist, D. T. Armstrong, and R. J. Norman, “Expression of leptin and its receptor in the murine ovary: possible role in the regulation of oocyte maturation,” Biology of Reproduction, vol. 66, no. 5, pp. 1548–1554, 2002. View at Publisher · View at Google Scholar
  146. J. E. Swain, R. L. Dunn, D. McConnell, J. Gonzalez-Martinez, and G. D. Smith, “Direct effects of leptin on mouse reproductive function: regulation of follicular, oocyte, and embryo development,” Biology of Reproduction, vol. 71, no. 5, pp. 1446–1452, 2004. View at Publisher · View at Google Scholar · View at PubMed
  147. E. Lord, S. Ledoux, B. D. Murphy, D. Beaudry, and M. F. Palin, “Expression of adiponectin and its receptors in swine,” Journal of Animal Science, vol. 83, no. 3, pp. 565–578, 2005.
  148. S. Ledoux, D. B. Campos, F. L. Lopes, M. Dobias-Goff, M.-F. Palin, and B. D. Murphy, “Adiponectin induces periovulatory changes in ovarian follicular cells,” Endocrinology, vol. 147, no. 11, pp. 5178–5186, 2006. View at Publisher · View at Google Scholar · View at PubMed
  149. P. Tontonoz, E. Hu, J. Devine, E. G. Beale, and B. M. Spiegelman, “PPARγ2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene,” Molecular and Cellular Biology, vol. 15, no. 1, pp. 351–357, 1995.
  150. K. Schoonjans, J. Peinado-Onsurbe, and A.-M. Lefebvre et al., “PPARα and PPARγ activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene,” EMBO Journal, vol. 15, no. 19, pp. 5336–5348, 1996.
  151. S. R. Ross, R. A. Graves, and A. Greenstein et al., “A fat-specific enhancer is the primary determinant of gene expression for adipocyte P2 in vivo,” Proceedings of the National Academy of Sciences of the United States of America, vol. 87, no. 24, pp. 9590–9594, 1990. View at Publisher · View at Google Scholar
  152. M. Watanabe, K. Inukai, H. Katagiri, T. Awata, Y. Oka, and S. Katayama, “Regulation of PPARγ transcriptional activity in 3T3-L1 adipocytes,” Biochemical and Biophysical Research Communications, vol. 300, no. 2, pp. 429–436, 2003. View at Publisher · View at Google Scholar
  153. P. Tontonoz, L. Nagy, J. G. A. Alvarez, V. A. Thomazy, and R. M. Evans, “PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL,” Cell, vol. 93, no. 2, pp. 241–252, 1998. View at Publisher · View at Google Scholar
  154. G. Chinetti, F. G. Gbaguidi, and S. Griglio et al., “CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors,” Circulation, vol. 101, no. 20, pp. 2411–2417, 2000.
  155. J. J. Petrik, P. A. Gentry, J.-J. Feige, and J. LaMarre, “Expression and localization of thrombospondin-1 and -2 and their cell-surface receptor, CD36, during rat follicular development and formation of the corpus luteum,” Biology of Reproduction, vol. 67, no. 5, pp. 1522–1531, 2002. View at Publisher · View at Google Scholar
  156. J. Greenaway, P. A. Gentry, J.-J. Feige, J. LaMarre, and J. J. Petrik, “Thrombospondin and vascular endothelial growth factor are cyclically expressed in an inverse pattern during bovine ovarian follicle development,” Biology of Reproduction, vol. 72, no. 5, pp. 1071–1078, 2005. View at Publisher · View at Google Scholar · View at PubMed
  157. J. E. Murphy-Ullrich, “The de-adhesive activity of matricellular proteins: is intermediate cell adhesion an adaptive state?,” Journal of Clinical Investigation, vol. 107, no. 7, pp. 785–790, 2001. View at Publisher · View at Google Scholar
  158. S. Goicoechea, A. W. Orr, M. A. Pallero, P. Eggleton, and J. E. Murphy-Ullrich, “Thrombospondin mediates focal adhesion disassembly through interactions with cell surface calreticulin,” Journal of Biological Chemistry, vol. 275, no. 46, pp. 36358–36368, 2000. View at Publisher · View at Google Scholar · View at PubMed
  159. L. Nagy, P. Tontonoz, J. G. A. Alvarez, H. Chen, and R. M. Evans, “Oxidized LDL regulates macrophage gene expression through ligand activation of PPARγ,” Cell, vol. 93, no. 2, pp. 229–240, 1998. View at Publisher · View at Google Scholar
  160. M. Ricote, J. T. Huang, J. S. Welch, and C. K. Glass, “The peroxisome proliferator-activated receptorγ (PPARγ) as a regulator of monocyte/macrophage function,” Journal of Leukocyte Biology, vol. 66, no. 5, pp. 733–739, 1999.
  161. P.-A. Svensson, M. S. C. Johnson, C. Ling, L. M. S. Carlsson, H. Billig, and B. Carlsson, “Scavenger receptor class B type I in the rat ovary: possible role in high density lipoprotein cholesterol uptake and in the recognition of apoptotic granulosa cells,” Endocrinology, vol. 140, no. 6, pp. 2494–2500, 1999. View at Publisher · View at Google Scholar
  162. E. Reaven, A. Nomoto, S. Leers-Sucheta, R. Temel, D. L. Williams, and S. Azhar, “Expression and microvillar localization of scavenger receptor, class B, type I (a high density lipoprotein receptor) in luteinized and hormone- desensitized rat ovarian models,” Endocrinology, vol. 139, no. 6, pp. 2847–2856, 1998. View at Publisher · View at Google Scholar
  163. M. Ricote, J. Huang, and L. Fajas et al., “Expression of the peroxisome proliferator-activated receptor γ (PPARγ) in human atherosclerosis and regulation in macrophages by colony stimulating factors and oxidized low density lipoprotein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 13, pp. 7614–7619, 1998. View at Publisher · View at Google Scholar
  164. M. Ricote, A. C. Li, T. M. Willson, C. J. Kelly, and C. K. Glass, “The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation,” Nature, vol. 391, no. 6662, pp. 79–82, 1998. View at Publisher · View at Google Scholar · View at PubMed
  165. R. B. Clark, D. Bishop-Bailey, T. Estrada-Hernandez, T. Hla, L. Puddington, and S. J. Padula, “The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses,” Journal of Immunology, vol. 164, no. 3, pp. 1364–1371, 2000.
  166. Y. Azuma, M. Shinohara, P.-L. Wang, and K. Ohura, “15-deoxy-Δ12,14-prostaglandin J2 inhibits IL-10 and IL-12 production by macrophages,” Biochemical and Biophysical Research Communications, vol. 283, no. 2, pp. 344–346, 2001. View at Publisher · View at Google Scholar · View at PubMed
  167. P. Wang, P. O. Anderson, S. Chen, K. M. Paulsson, H.-O. Sjögren, and S. Li, “Inhibition of the transcription factors AP-1 and NF-κB in CD4 T cells by peroxisome proliferator-activated receptor γ ligands,” International Immunopharmacology, vol. 1, no. 4, pp. 803–812, 2001. View at Publisher · View at Google Scholar
  168. D. G. Alleva, E. B. Johnson, F. M. Lio, S. A. Boehme, P. J. Conlon, and P. D. Crowe, “Regulation of murine macrophage proinflammatory and anti-inflammatory cytokines by ligands for peroxisome proliferator-activated receptor-γ: counter-regulatory activity by IFN-γ,” Journal of Leukocyte Biology, vol. 71, no. 4, pp. 677–685, 2002.
  169. M. Okada, S. F. Yan, and D. J. Pinsky, “Peroxisome proliferator-activated receptor-γ (PPAR-γ) activation suppresses ischemic induction of Egr-1 and its inflammatory gene targets,” FASEB Journal, vol. 16, no. 14, pp. 1861–1868, 2002. View at Publisher · View at Google Scholar · View at PubMed
  170. B. Hinz, K. Brune, and A. Pahl, “15-deoxy-Δ12,14-prostaglandin J2 inhibits the expression of proinflammatory genes in human blood monocytes via a PPAR-γ-independent mechanism,” Biochemical and Biophysical Research Communications, vol. 302, no. 2, pp. 415–420, 2003. View at Publisher · View at Google Scholar
  171. K. Asada, S. Sasaki, T. Suda, K. Chida, and H. Nakamura, “Antiinflammatory roles of peroxisome proliferator-activated receptor γ in human alveolar macrophages,” American Journal of Respiratory and Critical Care Medicine, vol. 169, no. 2, pp. 195–200, 2004. View at Publisher · View at Google Scholar · View at PubMed
  172. G. Chinetti, J.-C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors (PPARs): nuclear receptors at the crossroads between lipid metabolism and inflammation,” Inflammation Research, vol. 49, no. 10, pp. 497–505, 2000. View at Publisher · View at Google Scholar
  173. P. Delerive, J.-C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors in inflammation control,” Journal of Endocrinology, vol. 169, no. 3, pp. 453–459, 2001. View at Publisher · View at Google Scholar
  174. P. Henson, “Suppression of macrophage inflammatory responses by PPARs,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 11, pp. 6295–6296, 2003. View at Publisher · View at Google Scholar · View at PubMed
  175. B. Zahorska-Markiewicz, J. Janowska, M. Olszanecka-Glinianowicz, and A. Zurakowski, “Serum concentrations of TNF-α and soluble TNF-α receptors in obesity,” International Journal of Obesity, vol. 24, no. 11, pp. 1392–1395, 2000. View at Publisher · View at Google Scholar
  176. M. Olszanecka-Glinianowicz, B. Zahorska-Markiewicz, J. Janowska, and A. Zurakowski, “Serum concentrations of nitric oxide, tumor necrosis factor (TNF)-α and TNF soluble receptors in women with overweight and obesity,” Metabolism: Clinical and Experimental, vol. 53, no. 10, pp. 1268–1273, 2004. View at Publisher · View at Google Scholar
  177. G. S. Hotamisligil, N. S. Shargill, and B. M. Spiegelman, “Adipose expression of tumor necrosis factor-α: direct role in obesity-linked insulin resistance,” Science, vol. 259, no. 5091, pp. 87–91, 1993. View at Publisher · View at Google Scholar
  178. J. M. Stephens, J. Lee, and P. F. Pilch, “Tumor necrosis factor-α-induced insulin resistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction,” Journal of Biological Chemistry, vol. 272, no. 2, pp. 971–976, 1997. View at Publisher · View at Google Scholar
  179. G. Kroder, B. Bossenmaier, and M. Kellerer et al., “Tumor necrosis factor-α- and hyperglycemia-induced insulin resistance: evidence for different mechanisms and different effects on insulin signaling,” Journal of Clinical Investigation, vol. 97, no. 6, pp. 1471–1477, 1996. View at Publisher · View at Google Scholar
  180. J. S. Yudkin, M. Kumari, S. E. Humphries, and V. Mohamed-Ali, “Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link?,” Atherosclerosis, vol. 148, no. 2, pp. 209–214, 2000. View at Publisher · View at Google Scholar
  181. M. Olszanecka-Glinianowicz, M. Banaś, and B. Zahorska-Markiewicz et al., “Is the polycystic ovary syndrome associated with chronic inflammation per se?,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 133, no. 2, pp. 197–202, 2007. View at Publisher · View at Google Scholar · View at PubMed
  182. Y.-F. Zhang, Y.-S. Yang, and J. Hong et al., “Elevated serum levels of interleukin-18 are associated with insulin resistance in women with polycystic ovary syndrome,” Endocrine, vol. 29, no. 3, pp. 419–423, 2006. View at Publisher · View at Google Scholar · View at PubMed
  183. P. O. Szapary, L. T. Bloedon, and F. F. Samaha et al., “Effects of pioglitazone on lipoproteins, inflammatory markers, and adipokines in nondiabetic patients with metabolic syndrome,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 1, pp. 182–188, 2006. View at Publisher · View at Google Scholar · View at PubMed
  184. F. F. Samaha, P. O. Szapary, and N. Iqbal et al., “Effects of rosiglitazone on lipids, adipokines, and inflammatory markers in nondiabetic patients with low high-density lipoprotein cholesterol and metabolic syndrome,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 3, pp. 624–630, 2006. View at Publisher · View at Google Scholar · View at PubMed
  185. K. Esposito, M. Ciotola, and D. Carleo et al., “Effect of rosiglitazone on endothelial function and inflammatory markers in patients with the metabolic syndrome,” Diabetes Care, vol. 29, no. 5, pp. 1071–1076, 2006. View at Publisher · View at Google Scholar · View at PubMed
  186. T.-D. Wang, W.-J. Chen, J.-W. Lin, M.-F. Chen, and Y.-T. Lee, “Effects of Rosiglitazone on endothelial function, C-reactive protein, and components of the metabolic syndrome in nondiabetic patients with the metabolic syndrome,” American Journal of Cardiology, vol. 93, no. 3, pp. 362–365, 2004. View at Publisher · View at Google Scholar · View at PubMed
  187. T.-D. Wang, W.-J. Chen, W.-C. Cheng, J.-W. Lin, M.-F. Chen, and Y.-T. Lee, “Relation of improvement in endothelium-dependent flow-mediated vasodilation after rosiglitazone to changes in asymmetric dimethylarginine, endothelin-1, and C-reactive protein in nondiabetic patients with the metabolic syndrome,” American Journal of Cardiology, vol. 98, no. 8, pp. 1057–1062, 2006. View at Publisher · View at Google Scholar · View at PubMed
  188. I. Tarkun, B. Çetinarslan, E. Türemen, T. Şahin, Z. Cantürk, and B. Komsuoğlu, “Effect of rosiglitazone on insulin resistance, C-reactive protein and endothelial function in non-obese young women with polycystic ovary syndrome,” European Journal of Endocrinology, vol. 153, no. 1, pp. 115–121, 2005. View at Publisher · View at Google Scholar · View at PubMed
  189. K. Rautio, J. S. Tapanainen, A. Ruokonen, and L. C. Morin-Papunen, “Rosiglitazone treatment alleviates inflammation and improves liver function in overweight women with polycystic ovary syndrome: a randomized placebo-controlled study,” Fertility and Sterility, vol. 87, no. 1, pp. 202–206, 2007. View at Publisher · View at Google Scholar · View at PubMed
  190. P. Hellberg, P. Thomsen, P. O. Janson, and M. Brannstrom, “Leukocyte supplementation increases the luteinizing hormone-induced ovulation rate in the in vitro-perfused rat ovary,” Biology of Reproduction, vol. 44, no. 5, pp. 791–797, 1991. View at Publisher · View at Google Scholar
  191. M. Brannstrom, G. Mayrhofer, and S. A. Robertson, “Localization of leukocyte subsets in the rat ovary during the periovulatory period,” Biology of Reproduction, vol. 48, no. 2, pp. 277–286, 1993. View at Publisher · View at Google Scholar
  192. K. H. Van der Hoek, S. Maddocks, C. M. Woodhouse, N. Van Rooijen, S. A. Robertson, and R. J. Norman, “Intrabursal injection of clodronate liposomes causes macrophage depletion and inhibits ovulation in the mouse ovary,” Biology of Reproduction, vol. 62, no. 4, pp. 1059–1066, 2000. View at Publisher · View at Google Scholar
  193. P. E. Cohen, K. Nishimura, L. Zhu, and J. W. Pollard, “Macrophages: important accessory cells for reproductive function,” Journal of Leukocyte Biology, vol. 66, no. 5, pp. 765–772, 1999.
  194. M. Brännström and P. O. Janson, “The biochemistry of ovulation,” in Ovarian Endocrinology, pp. 133–166, Blackwell Science, Oxford, UK, 1991.
  195. R. Takaya, T. Fukaya, H. Sasano, T. Suzuki, M. Tamura, and A. Yajima, “Macrophages in normal cycling human ovaries; immunohistochemical localization and characterization,” Human Reproduction, vol. 12, no. 7, pp. 1508–1512, 1997. View at Publisher · View at Google Scholar
  196. E. Y. Anteby, A. Hurwitz, and O. Korach et al., “Human follicular nitric oxide pathway: relationship to follicular size, oestradiol concentrations and ovarian blood flow,” Human Reproduction, vol. 11, no. 9, pp. 1947–1951, 1996.
  197. C. Battaglia, M. Salvatori, N. Maxia, F. Petraglia, F. Facchinetti, and A. Volpe, “Adjuvant L-arginine treatment for in-vitro fertilization in poor responder patients,” Human Reproduction, vol. 14, no. 7, pp. 1690–1697, 1999. View at Publisher · View at Google Scholar
  198. D. G. Lemay and D. H. Hwang, “Genome-wide identification of peroxisome proliferator response elements using integrated computational genomics,” Journal of Lipid Research, vol. 47, no. 7, pp. 1583–1587, 2006. View at Publisher · View at Google Scholar · View at PubMed
  199. Y.-S. Tsai and N. Maeda, “PPARγ: a critical determinant of body fat distribution in humans and mice,” Trends in Cardiovascular Medicine, vol. 15, no. 3, pp. 81–85, 2005. View at Publisher · View at Google Scholar · View at PubMed
  200. M. Stumvoll and H. Häring, “The peroxisome proliferator-activated receptor-γ2 Pro12Ala polymorphism,” Diabetes, vol. 51, no. 8, pp. 2341–2347, 2002. View at Publisher · View at Google Scholar
  201. P. D. G. Miles, Y. Barak, W. He, R. M. Evans, and J. M. Olefsky, “Improved insulin-sensitivity in mice heterozygous for PPAR-γ deficiency,” Journal of Clinical Investigation, vol. 105, no. 3, pp. 287–292, 2000. View at Publisher · View at Google Scholar
  202. J. Masugi, Y. Tamori, H. Mori, T. Koike, and M. Kasuga, “Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-γ 2 on thiazolidinedione-induced adipogenesis,” Biochemical and Biophysical Research Communications, vol. 268, no. 1, pp. 178–182, 2000. View at Publisher · View at Google Scholar · View at PubMed
  203. H. J. Antoine, M. Pall, B. C. Trader, Y.-D. I. Chen, R. Azziz, and M. O. Goodarzi, “Genetic variants in peroxisome proliferator-activated receptor γ influence insulin resistance and testosterone levels in normal women, but not those with polycystic ovary syndrome,” Fertility and Sterility, vol. 87, no. 4, pp. 862–869, 2007. View at Publisher · View at Google Scholar · View at PubMed
  204. M. Mitkov, B. Pehlivanov, and D. Terzieva, “Metformin versus rosiglitazone in the treatment of polycystic ovary syndrome,” European Journal of Obstetrics Gynecology and Reproductive Biology, vol. 126, no. 1, pp. 93–98, 2006. View at Publisher · View at Google Scholar · View at PubMed
  205. N. A. Cataldo, F. Abbasi, and T. L. McLaughlin et al., “Metabolic and ovarian effects of rosiglitazone treatment for 12 weeks in insulin-resistant women with polycystic ovary syndrome,” Human Reproduction, vol. 21, no. 1, pp. 109–120, 2006. View at Publisher · View at Google Scholar · View at PubMed
  206. A. Lemay, S. Dodin, L. Turcot, F. Déchêne, and J.-C. Forest, “Rosiglitazone and ethinyl estradiol/cyproterone acetate as single and combined treatment of overweight women with polycystic ovary syndrome and insulin resistance,” Human Reproduction, vol. 21, no. 1, pp. 121–128, 2006. View at Publisher · View at Google Scholar · View at PubMed
  207. R. V. Mehta, K. S. Patel, and M. S. Coffler et al., “Luteinizing hormone secretion is not influenced by insulin infusion in women with polycystic ovary syndrome despite improved insulin sensitivity during pioglitazone treatment,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 4, pp. 2136–2141, 2005. View at Publisher · View at Google Scholar · View at PubMed