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PPAR Research
Volume 2016 (2016), Article ID 6218637, 10 pages
http://dx.doi.org/10.1155/2016/6218637
Research Article

Timcodar (VX-853) Is a Non-FKBP12 Binding Macrolide Derivative That Inhibits PPARγ and Suppresses Adipogenesis

1Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA
2Center for Drug Design and Development, Department of Medicinal & Biological Chemistry, University of Toledo College of Pharmacy and Pharmaceutical Sciences, Toledo, OH 43606, USA
3Center for Diabetes and Endocrine Research, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, OH 43614, USA

Received 8 January 2016; Accepted 27 March 2016

Academic Editor: Xu Shen

Copyright © 2016 Terry D. Hinds Jr. 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. T. D. Hinds Jr., L. A. Stechschulte, H. A. Cash et al., “Protein phosphatase 5 mediates lipid metabolism through reciprocal control of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ (PPARγ),” The Journal of Biological Chemistry, vol. 286, no. 50, pp. 42911–42922, 2011. View at Publisher · View at Google Scholar · View at Scopus
  2. L. A. Stechschulte, T. D. Hinds, S. S. Ghanem, W. Shou, S. M. Najjar, and E. R. Sanchez, “FKBP51 reciprocally regulates GRalpha and PPARgamma activation via the Akt-p38 pathway,” Molecular Endocrinology, vol. 28, no. 8, pp. 1254–1264, 2014. View at Publisher · View at Google Scholar
  3. L. A. Stechschulte, T. D. Hinds Jr., S. S. Khuder, W. Shou, S. M. Najjar, and E. R. Sanchez, “FKBP51 controls cellular adipogenesis through p38 kinase-mediated phosphorylation of GRα and PPARγ,” Molecular Endocrinology, vol. 28, no. 8, pp. 1265–1275, 2014. View at Publisher · View at Google Scholar · View at Scopus
  4. M. Warrier, T. D. Hinds Jr., K. J. Ledford et al., “Susceptibility to diet-induced hepatic steatosis and glucocorticoid resistance in FK506-binding protein 52-deficient mice,” Endocrinology, vol. 151, no. 7, pp. 3225–3236, 2010. View at Publisher · View at Google Scholar · View at Scopus
  5. D. MacMillan, “FK506 binding proteins: cellular regulators of intracellular Ca2+ signalling,” European Journal of Pharmacology, vol. 700, no. 1–3, pp. 181–193, 2013. View at Publisher · View at Google Scholar · View at Scopus
  6. M. W. Harding, “Immunophilins, mTOR, and pharmacodynamic strategies for a targeted, cancer therapy,” Clinical Cancer Research, vol. 9, no. 8, pp. 2882–2886, 2003. View at Google Scholar · View at Scopus
  7. M. D. DeBoer, “Obesity, systemic inflammation, and increased risk for cardiovascular disease and diabetes among adolescents: a need for screening tools to target interventions,” Nutrition, vol. 29, no. 2, pp. 379–386, 2013. View at Publisher · View at Google Scholar · View at Scopus
  8. J.-M. Renoir, C. Radanyi, L. E. Faber, and E.-E. Baulieu, “The non-DNA-binding heterooligomeric form of mammalian steroid hormone receptors contains a hsp90-bound 59-kilodalton protein,” The Journal of Biological Chemistry, vol. 265, no. 18, pp. 10740–10745, 1990. View at Google Scholar · View at Scopus
  9. I. M. Wolf, S. Periyasamy, T. Hinds Jr., W. Yong, W. Shou, and E. R. Sanchez, “Targeted ablation reveals a novel role of FKBP52 in gene-specific regulation of glucocorticoid receptor transcriptional activity,” Journal of Steroid Biochemistry and Molecular Biology, vol. 113, no. 1-2, pp. 36–45, 2009. View at Publisher · View at Google Scholar · View at Scopus
  10. W.-C. Yeh, B. E. Bierer, and S. L. McKnight, “Rapamycin inhibits clonal expansion and adipogenic differentiation of 3T3-L1 cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 92, no. 24, pp. 11086–11090, 1995. View at Publisher · View at Google Scholar · View at Scopus
  11. N. A. Clipstone and G. R. Crabtree, “Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation,” Nature, vol. 357, no. 6380, pp. 695–697, 1992. View at Publisher · View at Google Scholar · View at Scopus
  12. J. Liu, J. D. Farmer Jr., W. S. Lane, J. Friedman, I. Weissman, and S. L. Schreiber, “Calcineurin is a common target of cyclophilin-cyclosporin a and FKBP-FK506 complexes,” Cell, vol. 66, no. 4, pp. 807–815, 1991. View at Publisher · View at Google Scholar · View at Scopus
  13. S. H. Snyder and D. M. Sabatini, “Immunophilins and the nervous system,” Nature Medicine, vol. 1, no. 1, pp. 32–37, 1995. View at Publisher · View at Google Scholar · View at Scopus
  14. J. W. Neal and N. A. Clipstone, “Calcineurin mediates the calcium-dependent inhibition of adipocyte differentiation in 3T3-L1 cells,” The Journal of Biological Chemistry, vol. 277, no. 51, pp. 49776–49781, 2002. View at Publisher · View at Google Scholar · View at Scopus
  15. E. J. Brown, M. W. Albers, T. B. Shin et al., “A mammalian protein targeted by G1-arresting rapamycin-receptor complex,” Nature, vol. 369, no. 6483, pp. 756–758, 1994. View at Publisher · View at Google Scholar · View at Scopus
  16. D. M. Sabatini, H. Erdjument-Bromage, M. Lui, P. Tempst, and S. H. Snyder, “RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs,” Cell, vol. 78, no. 1, pp. 35–43, 1994. View at Publisher · View at Google Scholar · View at Scopus
  17. H. J. Cho, J. Park, H. W. Lee, Y. S. Lee, and J. B. Kim, “Regulation of adipocyte differentiation and insulin action with rapamycin,” Biochemical and Biophysical Research Communications, vol. 321, no. 4, pp. 942–948, 2004. View at Publisher · View at Google Scholar · View at Scopus
  18. M. I. Lefterova, A. K. Haakonsson, M. A. Lazar, and S. Mandrup, “PPARγ and the global map of adipogenesis and beyond,” Trends in Endocrinology and Metabolism, vol. 25, no. 6, pp. 293–302, 2014. View at Publisher · View at Google Scholar · View at Scopus
  19. E. Hu, J. B. Kim, P. Sarraf, and B. M. Spiegelman, “Inhibition of adipogenesis through MAP kinase-mediated phosphorylation of PPARγ,” Science, vol. 274, no. 5295, pp. 2100–2103, 1996. View at Publisher · View at Google Scholar · View at Scopus
  20. T. H. Davies, Y.-M. Ning, and E. R. Sánchez, “A new first step in activation of steroid receptors. Hormone-induced switching of FKBP51 and FKBP52 immunophilins,” The Journal of Biological Chemistry, vol. 277, no. 7, pp. 4597–4600, 2002. View at Publisher · View at Google Scholar · View at Scopus
  21. Y.-M. Ning and E. R. Sánchez, “Potentiation of glucocorticoid receptor-mediated gene expression by the immunophilin ligands FK506 and rapamycin,” The Journal of Biological Chemistry, vol. 268, no. 9, pp. 6073–6076, 1993. View at Google Scholar · View at Scopus
  22. K. H. Schreiber, D. Ortiz, E. C. Academia, A. C. Anies, C.-Y. Liao, and B. K. Kennedy, “Rapamycin-mediated mTORC2 inhibition is determined by the relative expression of FK506-binding proteins,” Aging Cell, vol. 14, no. 2, pp. 265–273, 2015. View at Publisher · View at Google Scholar · View at Scopus
  23. G. Baughman, G. J. Wiederrecht, N. F. Campbell, M. M. Martin, and S. Bourgeois, “FKBP51, a novel T-cell-specific immunophilin capable of calcineurin inhibition,” Molecular and Cellular Biology, vol. 15, no. 8, pp. 4395–4402, 1995. View at Publisher · View at Google Scholar · View at Scopus
  24. D. A. Peattie, M. W. Harding, M. A. Fleming et al., “Expression and characterization of human FKBP52, an immunophilin that associates with the 90-kDa heat shock protein and is a component of steroid receptor complexes,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 22, pp. 10974–10978, 1992. View at Publisher · View at Google Scholar · View at Scopus
  25. B. G. Gold, “FK506 and the role of immunophilins in nerve regeneration,” Molecular Neurobiology, vol. 15, no. 3, pp. 285–306, 1997. View at Publisher · View at Google Scholar · View at Scopus
  26. B. G. Gold, D. M. Armistead, and M.-S. Wang, “Non-FK506-binding protein-12 neuroimmunophilin ligands increase neurite elongation and accelerate nerve regeneration,” Journal of Neuroscience Research, vol. 80, no. 1, pp. 56–65, 2005. View at Publisher · View at Google Scholar · View at Scopus
  27. B. G. Gold, J. Voda, X. Yu, G. McKeon, and D. N. Bourdette, “FK506 and a nonimmunosuppressant derivative reduce axonal and myelin damage in experimental autoimmune encephalomyelitis: neuroimmunophilin ligand-mediated neuroprotection in a model of multiple sclerosis,” Journal of Neuroscience Research, vol. 77, no. 3, pp. 367–377, 2004. View at Publisher · View at Google Scholar · View at Scopus
  28. B. G. Gold, V. Densmore, W. Shou, M. M. Matzuk, and H. S. Gordon, “Immunophilin FK506-binding protein 52 (not FK506-binding protein 12) mediates the neurotrophic action of FK506,” Journal of Pharmacology and Experimental Therapeutics, vol. 289, no. 3, pp. 1202–1210, 1999. View at Google Scholar · View at Scopus
  29. B. G. Gold, “FK506 and the role of the immunophilin FKBP-52 in nerve regeneration,” Drug Metabolism Reviews, vol. 31, no. 3, pp. 649–663, 1999. View at Publisher · View at Google Scholar · View at Scopus
  30. R. E. Babine, J. E. Villafranca, and B. G. Gold, “FKBP immunophilin patents for neurological disorders,” Expert Opinion on Therapeutic Patents, vol. 15, no. 5, pp. 555–573, 2005. View at Publisher · View at Google Scholar · View at Scopus
  31. D. G. Cole, S. Ogenstad, and P. Chaturvedi, “Pharmacological activities of neurophilin ligands,” in Immunophilins in the Brain: FKBP-Ligands: Novel Strategies for the Treatment of Neurodegenerative Disorders, pp. 109–116, Prous Science, Barcelona, Spain, 2000. View at Google Scholar
  32. M. Polydefkis, M. Sirdofsky, P. Hauer, B. G. Petty, B. Murinson, and J. C. McArthur, “Factors influencing nerve regeneration in a trial of timcodar dimesylate,” Neurology, vol. 66, no. 2, pp. 259–261, 2006. View at Publisher · View at Google Scholar · View at Scopus
  33. T. D. Hinds, L. A. Stechschulte, F. Elkhairi, and E. R. Sanchez, “Analysis of FK506, timcodar (VX-853) and FKBP51 and FKBP52 chaperones in control of glucocorticoid receptor activity and phosphorylation,” Pharmacology Research & Perspectives, vol. 2, no. 6, 2014. View at Publisher · View at Google Scholar
  34. R. Gopalakrishnan, C. Kozany, S. Gaali et al., “Evaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52,” Journal of Medicinal Chemistry, vol. 55, no. 9, pp. 4114–4122, 2012. View at Publisher · View at Google Scholar · View at Scopus
  35. S. Periyasamy, T. Hinds, L. Shemshedini, W. Shou, and E. R. Sanchez, “FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A,” Oncogene, vol. 29, no. 11, pp. 1691–1701, 2010. View at Publisher · View at Google Scholar · View at Scopus
  36. S. L. Schreiber, “Chemistry and biology of the immunophilins and their immunosuppressive ligands,” Science, vol. 251, no. 4991, pp. 283–287, 1991. View at Publisher · View at Google Scholar · View at Scopus
  37. K. John, J. S. Marino, E. R. Sanchez, and T. D. Hinds Jr., “The glucocorticoid receptor: cause of or cure for obesity?” American Journal of Physiology—Endocrinology and Metabolism, vol. 310, no. 4, pp. E249–E257, 2016. View at Publisher · View at Google Scholar
  38. D. Duma, C. M. Jewell, and J. A. Cidlowski, “Multiple glucocorticoid receptor isoforms and mechanisms of post-translational modification,” Journal of Steroid Biochemistry and Molecular Biology, vol. 102, no. 1–5, pp. 11–21, 2006. View at Publisher · View at Google Scholar · View at Scopus
  39. T. D. Hinds Jr., S. Ramakrishnan, H. A. Cash et al., “Discovery of glucocorticoid receptor-β in mice with a role in metabolism,” Molecular Endocrinology, vol. 24, no. 9, pp. 1715–1727, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. L. A. Stechschulte, L. Wuescher, J. S. Marino, J. W. Hill, C. Eng, and T. D. Hinds Jr., “Glucocorticoid receptor β stimulates Akt1 growth pathway by attenuation of PTEN,” The Journal of Biological Chemistry, vol. 289, no. 25, pp. 17885–17894, 2014. View at Publisher · View at Google Scholar
  41. T. D. Hinds, B. Peck, E. Shek et al., “Overexpression of glucocorticoid receptor β enhances myogenesis and reduces catabolic gene expression,” International Journal of Molecular Sciences, vol. 17, no. 2, p. 232, 2016. View at Publisher · View at Google Scholar
  42. I. Rogatsky, J. M. Trowbridge, and M. J. Garabedian, “Glucocorticoid receptor-mediated cell cycle arrest is achieved through distinct cell-specific transcriptional regulatory mechanisms,” Molecular and Cellular Biology, vol. 17, no. 6, pp. 3181–3193, 1997. View at Publisher · View at Google Scholar · View at Scopus
  43. A. Yemelyanov, J. Czwornog, D. Chebotaev et al., “Tumor suppressor activity of glucocorticoid receptor in the prostate,” Oncogene, vol. 26, no. 13, pp. 1885–1896, 2007. View at Publisher · View at Google Scholar · View at Scopus
  44. X. Shi, W. Shi, Q. Li et al., “A glucocorticoid-induced leucine-zipper protein, GILZ, inhibits adipogenesis of mesenchymal cells,” EMBO Reports, vol. 4, no. 4, pp. 374–380, 2003. View at Publisher · View at Google Scholar · View at Scopus
  45. W. Zhang, N. Yang, and X.-M. Shi, “Regulation of mesenchymal stem cell osteogenic differentiation by glucocorticoid-induced leucine zipper (GILZ),” The Journal of Biological Chemistry, vol. 283, no. 8, pp. 4723–4729, 2008. View at Publisher · View at Google Scholar · View at Scopus
  46. C. M. Smas and H. S. Sul, “Pref-1, a protein containing EGF-like repeats, inhibits adipocyte differentiation,” Cell, vol. 73, no. 4, pp. 725–734, 1993. View at Publisher · View at Google Scholar · View at Scopus
  47. C. M. Smas and H. S. Sul, “Molecular mechanisms of adipocyte differentiation and inhibitory action of pref-1,” Critical Reviews in Eukaryotic Gene Expression, vol. 7, no. 4, pp. 281–298, 1997. View at Publisher · View at Google Scholar · View at Scopus
  48. P. Greenwel, S. Tanaka, D. Penkov et al., “Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins,” Molecular and Cellular Biology, vol. 20, no. 3, pp. 912–918, 2000. View at Publisher · View at Google Scholar · View at Scopus
  49. S. Natsuka, S. Akira, Y. Nishio et al., “Macrophage differentiation-specific expression of NF-IL6, a transcription factor for interleukin-6,” Blood, vol. 79, no. 2, pp. 460–466, 1992. View at Google Scholar · View at Scopus
  50. G. J. Darlington, S. E. Ross, and O. A. MacDougald, “The role of C/EBP genes in adipocyte differentiation,” The Journal of Biological Chemistry, vol. 273, no. 46, pp. 30057–30060, 1998. View at Publisher · View at Google Scholar · View at Scopus
  51. G.-R. Chang, Y.-Y. Wu, Y.-S. Chiu et al., “Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice,” Basic and Clinical Pharmacology and Toxicology, vol. 105, no. 3, pp. 188–198, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. O. V. Leontieva, G. Paszkiewicz, Z. N. Demidenko, and M. V. Blagosklonny, “Resveratrol potentiates rapamycin to prevent hyperinsulinemia and obesity in male mice on high fat diet,” Cell Death & Disease, vol. 4, article e472, 2013. View at Publisher · View at Google Scholar · View at Scopus
  53. T. D. Hinds Jr., K. Sodhi, C. Meadows et al., “Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21,” Obesity, vol. 22, no. 3, pp. 705–712, 2014. View at Publisher · View at Google Scholar · View at Scopus
  54. L. O’Brien, P. A. Hosick, K. John, D. E. Stec, and T. D. Hinds, “Biliverdin reductase isozymes in metabolism,” Trends in Endocrinology and Metabolism, vol. 26, no. 4, pp. 212–220, 2015. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Jamaluddin, S. Wang, I. Boldogh, B. Tian, and A. R. Brasier, “TNF-alpha-induced NF-kappaB/RelA Ser(276) phosphorylation and enhanceosome formation is mediated by an ROS-dependent PKAc pathway,” Cellular Signalling, vol. 19, no. 7, pp. 1419–1433, 2007. View at Google Scholar
  56. K. Makki, S. Taront, O. Molendi-Coste et al., “Beneficial metabolic effects of rapamycin are associated with enhanced regulatory cells in diet-induced obese mice,” PLoS ONE, vol. 9, no. 4, Article ID e92684, 2014. View at Publisher · View at Google Scholar · View at Scopus
  57. C. L. Gabriel, P. B. Smith, Y. V. Mendez-Fernandez, A. J. Wilhelm, A. M. Ye, and A. S. Major, “Autoimmune-mediated glucose intolerance in a mouse model of systemic lupus erythematosus,” American Journal of Physiology—Endocrinology and Metabolism, vol. 303, no. 11, pp. E1313–E1324, 2012. View at Publisher · View at Google Scholar · View at Scopus
  58. G.-R. Chang, Y.-S. Chiu, Y.-Y. Wu et al., “Rapamycin protects against high fat diet-induced obesity in C57BL/6J mice,” Journal of Pharmacological Sciences, vol. 109, no. 4, pp. 496–503, 2009. View at Publisher · View at Google Scholar · View at Scopus
  59. S. S. Deepa, M. E. Walsh, R. T. Hamilton et al., “Rapamycin modulates markers of mitochondrial biogenesis and fatty acid oxidation in the adipose tissue of db/db mice,” Journal of Biochemical and Pharmacological Research, vol. 1, no. 2, pp. 114–123, 2013. View at Google Scholar