The multifaceted factor peroxisome proliferator-activated receptor γ (PPARγ) in metabolism, immunity, and cancer

Archives of Pharmacal Research

Volumn 38, Issue 3, 2015, Pages 302-312

  Kim, Jung Hoon ^a   Song, Jaewhan ^a   Park, Kye Won ^b  

^a Yonsei University   (South Korea)

^b Sungkyunkwan University   (South Korea)

Author keywords

Cancer; Immunity; Metabolism; Obesity; PPAR

Indexed keywords

PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA;

APOPTOSIS; ATHEROSCLEROSIS; CELL PROLIFERATION; FOOD INTAKE; HOST RESISTANCE; HUMAN; HYPERTENSION; IMMUNOGENICITY; INSULIN RESISTANCE; LIPID METABOLISM; METABOLISM; OBESITY; PROTEIN FUNCTION; REVIEW; TUMOR IMMUNITY; ANIMAL; COMPLICATION; INCIDENCE; INFLAMMATION; METABOLIC DISEASES; NEOPLASMS; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY; PREVALENCE;

ANIMALS; CELL PROLIFERATION; HUMANS; INCIDENCE; INFLAMMATION; LIPID METABOLISM; METABOLIC DISEASES; NEOPLASMS; OBESITY; PPAR GAMMA; PREVALENCE;

EID: 84925481394     PISSN: 02536269     EISSN: 19763786     Source Type: Journal    
DOI: 10.1007/s12272-015-0559-x     Document Type: Review

References (116)

1. Appel, S., V. Mirakaj, A. Bringmann, M.M. Weck, F. Grunebach, and P. Brossart. 2005. PPAR-gamma agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-kappaB pathways. Blood 106(12): 3888-3894. doi: 10.1182/blood-2004-12-4709.
2. Bae, M.A., and B.J. Song. 2003. Critical role of c-Jun N-terminal protein kinase activation in troglitazone-induced apoptosis of human HepG2 hepatoma cells. Molecular Pharmacology 63(2): 401-408.
3. Balint, B.L., and L. Nagy. 2006. Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases. Endocrine, Metabolic & Immune Disorders: Drug Targets 6(1): 33-43.
4. Barak, Y., M.C. Nelson, E.S. Ong, Y.Z. Jones, P. Ruiz-Lozano, K.R. Chien, A. Koder, and R.M. Evans. 1999. PPAR gamma is required for placental, cardiac, and adipose tissue development. Molecular Cell 4(4): 585-595. doi: 10.1016/S1097-2765(00)80209-9.
5. Bartelt, A., and J. Heeren. 2014. Adipose tissue browning and metabolic health. Nature Reviews Endocrinology 10(1): 24-36. doi: 10.1038/nrendo.2013.204.
6. Battaglia, S., O. Maguire, J.L. Thorne, L.B. Hornung, C.L. Doig, S. Liu, L.E. Sucheston, et al. 2010. Elevated NCOR1 disrupts PPARalpha/gamma signaling in prostate cancer and forms a targetable epigenetic lesion. Carcinogenesis 31(9): 1650-1660. doi: 10.1093/carcin/bgq086.
7. Bonofiglio, D., S. Aquila, S. Catalano, S. Gabriele, M. Belmonte, E. Middea, H. Qi, et al. 2006. Peroxisome proliferator-activated receptor-gamma activates p53 gene promoter binding to the nuclear factor-kappaB sequence in human MCF7 breast cancer cells. Molecular Endocrinology 20(12): 3083-3092. doi: 10.1210/me.2006-0192.
8. Bren-Mattison, Y., A.M. Meyer, V. Van Putten, H. Li, K. Kuhn, R. Stearman, M. Weiser-Evans, R.A. Winn, L.E. Heasley, and R.A. Nemenoff. 2008. Antitumorigenic effects of peroxisome proliferator-activated receptor-gamma in non-small-cell lung cancer cells are mediated by suppression of cyclooxygenase-2 via inhibition of nuclear factor-kappaB. Molecular Pharmacology 73(3): 709-717. doi: 10.1124/mol.107.042002.
9. Campbell, M.J., C. Carlberg, and H.P. Koeffler. 2008. A role for the PPARgamma in cancer therapy. PPAR Research 2008: 314974. doi: 10.1155/2008/314974.
10. Cesario, R.M., J. Stone, W.C. Yen, R.P. Bissonnette, and W.W. Lamph. 2006. Differentiation and growth inhibition mediated via the RXR:PPARgamma heterodimer in colon cancer. Cancer Letters 240(2): 225-233. doi: 10.1016/j.canlet.2005.09.010.
11. Chawla, A., W.A. Boisvert, C.H. Lee, B.A. Laffitte, Y. Barak, S.B. Joseph, D. Liao, et al. 2001. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Molecular Cell 7(1): 161-171.
12. Chen, F., and L.E. Harrison. 2005. Ciglitazone-induced cellular anti-proliferation increases p27kip1 protein levels through both increased transcriptional activity and inhibition of proteasome degradation. Cellular Signalling 17(7): 809-816. doi: 10.1016/j.cellsig.2004.11.002.
13. Choi, J.H., A.S. Banks, J.L. Estall, S. Kajimura, P. Bostrom, D. Laznik, J.L. Ruas, et al. 2010. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature 466(7305): 451-456. doi: 10.1038/nature09291.
14. Choi, J.H., A.S. Banks, T.M. Kamenecka, S.A. Busby, M.J. Chalmers, N. Kumar, D.S. Kuruvilla, et al. 2011. Antidiabetic actions of a non-agonist PPARgamma ligand blocking Cdk5-mediated phosphorylation. Nature 477(7365): 477-481. doi: 10.1038/nature10383.
15. Cristancho, A.G., and M.A. Lazar. 2011. Forming functional fat: A growing understanding of adipocyte differentiation. Nature Reviews Molecular Cell Biology 12(11): 722-734. doi: 10.1038/nrm3198.
16. da Rocha Junior, L.F., A.T. Dantas, A.L. Duarte, M.J. de Melo Rego, R. Pitta Ida, and M.G. Pitta. 2013. PPARgamma agonists in adaptive immunity: What do immune disorders and their models have to tell us? PPAR Research 2013: 519724. doi: 10.1155/2013/519724.
17. DePaoli, A.M., L.S. Higgins, R.R. Henry, C. Mantzoros, and F.L. Dunn. 2014. Can a selective PPARgamma modulator improve glycemic control in patients with type 2 diabetes with fewer side effects compared with pioglitazone? Diabetes Care 37(7): 1918-1923. doi: 10.2337/dc13-2480.
18. Duan, S.Z., C.Y. Ivashchenko, S.E. Whitesall, L.G. D'Alecy, D.C. Duquaine, F.C. Brosius, F.J. Gonzalez, et al. 2007. Hypotension, lipodystrophy, and insulin resistance in generalized PPAR gamma-deficient mice rescued from embryonic lethality. Journal of Clinical Investigation 117(3): 812-822. doi: 10.1172/Jci28859.
19. Erdmann, E., B. Charbonnel, and R. Wilcox. 2009. Thiazolidinediones and cardiovascular risk - a question of balance. Current Cardiology Reviews 5(3): 155-165. doi: 10.2174/157340309788970333.
20. Farrow, B., and B.M. Evers. 2003. Activation of PPARgamma increases PTEN expression in pancreatic cancer cells. Biochem Biophys Res Commun 301(1): 50-53.
21. Feldman, P.L., M.H. Lambert, and B.R. Henke. 2008. PPAR modulators and PPAR pan agonists for metabolic diseases: The next generation of drugs targeting peroxisome proliferator-activated receptors? Current Topics in Medicinal Chemistry 8(9): 728-749.
22. Ferrante Jr, A.W. 2013. Macrophages, fat, and the emergence of immunometabolism. The Journal of Clinical Investigation 123(12): 4992-4993. doi: 10.1172/JCI73658.
23. Fisher, B.L., and P. Schauer. 2002. Medical and surgical options in the treatment of severe obesity. American Journal of Surgery 184(6B): 9S-16S.
24. Floyd, Z.E., and J.M. Stephens. 2004. Control of peroxisome proliferator-activated receptor gamma2 stability and activity by SUMOylation. Obesity Research 12(6): 921-928. doi: 10.1038/oby.2004.112.
25. Fredenrich, A., and P.A. Grimaldi. 2005. PPAR delta: An uncompletely known nuclear receptor. Diabetes & Metabolism 31(1): 23-27.
26. Fujita, M., T. Yagami, M. Fujio, C. Tohji, K. Takase, Y. Yamamoto, K. Sawada, M. Yamamori, and N. Okamura. 2011. Cytotoxicity of troglitazone through PPARgamma-independent pathway and p38 MAPK pathway in renal cell carcinoma. Cancer Letters 312(2): 219-227. doi: 10.1016/j.canlet.2011.08.010.
27. Gavrilova, O., M. Haluzik, K. Matsusue, J.J. Cutson, L. Johnson, K.R. Dietz, C.J. Nicol, C. Vinson, F.J. Gonzalez, and M.L. Reitman. 2003. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. Journal of Biological Chemistry 278(36): 34268-34276. doi: 10.1074/jbc.M300043200M300043200.
28. Govindarajan, R., L. Ratnasinghe, D.L. Simmons, E.R. Siegel, M.V. Midathada, L. Kim, P.J. Kim, R.J. Owens, and N.P. Lang. 2007. Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. Journal of Clinical Oncology 25(12): 1476-1481. doi: 10.1200/JCO.2006.07.2777.
29. Graham, D.J., R. Ouellet-Hellstrom, T.E. MaCurdy, F. Ali, C. Sholley, C. Worrall, and J.A. Kelman. 2010. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA 304(4): 411-418. doi: 10.1001/jama.2010.920.
30. Guri, A.J., S.K. Mohapatra, W.T. Horne 2nd, R. Hontecillas, and J. Bassaganya-Riera. 2010. The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease. BMC Gastroenterol 10: 60. doi: 10.1186/1471-230X-10-60.
31. Hammad, H., H.J. de Heer, T. Soullie, V. Angeli, F. Trottein, H.C. Hoogsteden, and B.N. Lambrecht. 2004. Activation of peroxisome proliferator-activated receptor-gamma in dendritic cells inhibits the development of eosinophilic airway inflammation in a mouse model of asthma. American Journal of Pathology 164(1): 263-271.
32. Hauser, S., G. Adelmant, P. Sarraf, H.M. Wright, E. Mueller, and B.M. Spiegelman. 2000. Degradation of the peroxisome proliferator-activated receptor gamma is linked to ligand-dependent activation. Journal of Biological Chemistry 275(24): 18527-18533. doi: 10.1074/jbc.M001297200M001297200.
33. He, W., Y. Barak, A. Hevener, P. Olson, D. Liao, J. Le, M. Nelson, E. Ong, J.M. Olefsky, and R.M. Evans. 2003. Adipose-specific peroxisome proliferator-activated receptor gamma knockout causes insulin resistance in fat and liver but not in muscle. Proceedings of the National Academy of Sciences USA 100(26): 15712-15717. doi: 10.1073/pnas.2536828100.
34. Hevener, A.L., W.M. He, Y. Barak, J. Le, G. Bandyopadhyay, P. Olson, J. Wilkes, R.M. Evans, and J. Olefsky. 2003. Muscle-specific Pparg deletion causes insulin resistance. Nature Medicine 9(12): 1491-1497. doi: 10.1038/Nm956.
35. Hill, J.O., H.R. Wyatt, G.W. Reed, and J.C. Peters. 2003. Obesity and the environment: where do we go from here? Science 299(5608): 853-855. doi: 10.1126/science.1079857299/5608/853.
36. Hong, J.W., and K.W. Park. 2010. Further understanding of fat biology: lessons from a fat fly. Experimental & Molecular Medicine 42(1): 12-20. doi: 10.3858/emm.2010.42.1.007.
37. Hontecillas, R., and J. Bassaganya-Riera. 2007. Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. The Journal of Immunology 178(5): 2940-2949.
38. Hwa, J.S., L. Mun, H.J. Kim, H.G. Seo, J.H. Lee, J.H. Kwak, D.U. Lee, and K.C. Chang. 2011. Genipin selectively inhibits TNF-alpha-activated VCAM-1 but not ICAM-1 expression by upregulation of PPAR-gamma in human endothelial cells. Korean Journal of Physiology and Pharmacology 15(3): 157-162. doi: 10.4196/kjpp.2011.15.3.157.
39. Jeong, Y., Y. Xie, W. Lee, A.L. Bookout, L. Girard, G. Raso, C. Behrens, et al. 2012. Research resource: Diagnostic and therapeutic potential of nuclear receptor expression in lung cancer. Molecular Endocrinology 26(8): 1443-1454. doi: 10.1210/me.2011-1382.
40. Jones, J.R., C. Barrick, K.A. Kim, J. Lindner, B. Blondeau, Y. Fujimoto, M. Shiota, R.A. Kesterson, B.B. Kahn, and M.A. Magnuson. 2005. Deletion of PPARgamma in adipose tissues of mice protects against high fat diet-induced obesity and insulin resistance. The Proceedings of the National Academy USA 102(17): 6207-6212. doi: 10.1073/pnas.0306743102.
41. Kebebew, E., Peng, M., Reiff, E., Treseler, P., Woeber, K., Clark, O.H., Greenspan, F.S., Lindsay, S., Duh, Q.Y., and Morita, E. 2006. A phase II trial of rosiglitazone in patients with thyroglobulin-positive and radioiodine-negative differentiated thyroid cancer. Surgery 140 (6):960-966. Discussion 966-967. doi: 10.1016/j.surg.2006.07.038.
42. Kidani, Y., and S.J. Bensinger. 2012. Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity. Immunological Reviews 249(1): 72-83. doi: 10.1111/j.1600-065X.2012.01153.x.
43. Kilroy, G.E., X. Zhang, and Z.E. Floyd. 2009. PPAR-gamma AF-2 domain functions as a component of a ubiquitin-dependent degradation signal. Obesity (Silver Spring) 17(4): 665-673. doi: 10.1038/oby.2008.616.
44. Kilroy, G., H. Kirk-Ballard, L.E. Carter, and Z.E. Floyd. 2012. The ubiquitin ligase Siah2 regulates PPARgamma activity in adipocytes. Endocrinology 153(3): 1206-1218. doi: 10.1210/en.2011-1725.
45. Kim, J.H., K.W. Park, E.W. Lee, W.S. Jang, J. Seo, S. Shin, K.A. Hwang, and J. Song. 2014. Suppression of PPARgamma through MKRN1-mediated ubiquitination and degradation prevents adipocyte differentiation. Cell Death and Differentiation 21(4): 594-603. doi: 10.1038/cdd.2013.181.
46. Kim, K.Y., S.S. Kim, and H.G. Cheon. 2006. Differential anti-proliferative actions of peroxisome proliferator-activated receptor-gamma agonists in MCF-7 breast cancer cells. Biochemical Pharmacology 72(5): 530-540. doi: 10.1016/j.bcp.2006.05.009.
47. Kim, Y., N. Suh, M. Sporn, and J.C. Reed. 2002. An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis. Journal of Biological Chemistry 277(25): 22320-22329. doi: 10.1074/jbc.M202458200.
48. Kiss, M., Z. Czimmerer, and L. Nagy. 2013. The role of lipid-activated nuclear receptors in shaping macrophage and dendritic cell function: From physiology to pathology. The Journal of Allergy and Clinical Immunology 132(2): 264-286. doi: 10.1016/j.jaci.2013.05.044.
49. Klotz, L., S. Burgdorf, I. Dani, K. Saijo, J. Flossdorf, S. Hucke, J. Alferink, et al. 2009. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. Journal of Experimental Medicine 206(10): 2079-2089. doi: 10.1084/jem.20082771.
50. Koeffler, H.P. 2003. Peroxisome proliferator-activated receptor gamma and cancers. Clinical Cancer Research 9(1): 1-9.
51. Kopelman, P.G. 2000. Obesity as a medical problem. Nature 404(6778): 635-643. doi: 10.1038/35007508.
52. Lehmann, J.M., L.B. Moore, T.A. Smith-Oliver, W.O. Wilkison, T.M. Willson, and S.A. Kliewer. 1995. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). Journal of Biological Chemistry 270(22): 12953-12956.
53. Liu, Y., Z.A. Zhu, S.N. Zhang, J. Mou, L. Liu, T. Cui, and D.S. Pei. 2013. Combinational effect of PPARgamma agonist and RXR agonist on the growth of SGC7901 gastric carcinoma cells in vitro. Tumour Biology 34(4): 2409-2418. doi: 10.1007/s13277-013-0791-2.
54. Lubet, R.A., S.M. Fischer, V.E. Steele, M.M. Juliana, R. Desmond, and C.J. Grubbs. 2008. Rosiglitazone, a PPAR gamma agonist: potent promoter of hydroxybutyl(butyl)nitrosamine-induced urinary bladder cancers. International Journal of Cancer 123(10): 2254-2259. doi: 10.1002/ijc.23765.
55. Manolagas, S.C. 1998. Cellular and molecular mechanisms of osteoporosis. Aging (Milano) 10(3): 182-190.
56. Mansure, J.J., R. Nassim, S. Chevalier, K. Szymanski, J. Rocha, S. Aldousari, and W. Kassouf. 2013. A novel mechanism of PPAR gamma induction via EGFR signalling constitutes rational for combination therapy in bladder cancer. PLoS ONE 8(2): e55997. doi: 10.1371/journal.pone.0055997.
57. Matsusue, K., M. Haluzik, G. Lambert, S.H. Yim, O. Gavrilova, J.M. Ward, B. Brewer Jr, M.L. Reitman, and F.J. Gonzalez. 2003. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. Journal of Clinical Investigation 111(5): 737-747. doi: 10.1172/JCI17223.
58. McAlpine, C.A., Y. Barak, I. Matise, and R.T. Cormier. 2006. Intestinal-specific PPARgamma deficiency enhances tumorigenesis in ApcMin/+ mice. International Journal of Cancer 119(10): 2339-2346. doi: 10.1002/ijc.22115.
59. McKinnon, B., N.A. Bersinger, and M.D. Mueller. 2012. Peroxisome proliferating activating receptor gamma-independent attenuation of interleukin 6 and interleukin 8 secretion from primary endometrial stromal cells by thiazolidinediones. Fertility and Sterility 97(3): 657-664. doi: 10.1016/j.fertnstert.2011.12.001.
60. Moerman, E.J., K. Teng, D.A. Lipschitz, and B. Lecka-Czernik. 2004. Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways. Aging Cell 3(6): 379-389. doi: 10.1111/j.1474-9728.2004.00127.x.
61. Motomura, W., T. Okumura, N. Takahashi, T. Obara, and Y. Kohgo. 2000. Activation of peroxisome proliferator-activated receptor gamma by troglitazone inhibits cell growth through the increase of p27KiP1 in human pancreatic carcinoma cells. Cancer Research 60(19): 5558-5564.
62. Mueller, E., M. Smith, P. Sarraf, T. Kroll, A. Aiyer, D.S. Kaufman, W. Oh, et al. 2000. Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. The Proceedings of the National Academy USA 97(20): 10990-10995. doi: 10.1073/pnas.180329197.
63. Nagy, L., P. Tontonoz, J.G. Alvarez, H. Chen, and R.M. Evans. 1998. Oxidized LDL regulates macrophage gene expression through ligand activation of PPARgamma. Cell 93(2): 229-240.
64. Nencioni, A., F. Grunebach, A. Zobywlaski, C. Denzlinger, W. Brugger, and P. Brossart. 2002. Dendritic cell immunogenicity is regulated by peroxisome proliferator-activated receptor gamma. Journal of Immunology 169(3): 1228-1235.
65. Nesto, R.W., D. Bell, R.O. Bonow, V. Fonseca, S.M. Grundy, E.S. Horton, M. Le Winter, et al. 2004. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 27(1): 256-263.
66. Nguyen, M.T., A. Chen, W.J. Lu, W. Fan, P.P. Li, D.Y. Oh, and D. Patsouris. 2012. Regulation of chemokine and chemokine receptor expression by PPARgamma in adipocytes and macrophages. PLoS ONE 7(4): e34976. doi: 10.1371/journal.pone.0034976.
67. Nissen, S.E., and K. Wolski. 2007. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. New England Journal of Medicine 356(24): 2457-2471. doi: 10.1056/NEJMoa072761.
68. Norris, A.W., L. Chen, S.J. Fisher, I. Szanto, M. Ristow, A.C. Jozsi, M.F. Hirshman, et al. 2003. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. Journal of Clinical Investigation 112(4): 608-618. doi: 10.1172/JCI17305.
69. Odegaard, J.I., and A. Chawla. 2011. Alternative macrophage activation and metabolism. Annual Review of Pathology: Mechanisms of Disease 6: 275-297. doi: 10.1146/annurev-pathol-011110-130138.
70. Odegaard, J.I., R.R. Ricardo-Gonzalez, M.H. Goforth, C.R. Morel, V. Subramanian, L. Mukundan, A. Red Eagle, et al. 2007. Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447(7148): 1116-1120. doi: 10.1038/nature05894.
71. Ogino, S., K. Shima, Y. Baba, K. Nosho, N. Irahara, S. Kure, L. Chen, et al. 2009. Colorectal cancer expression of peroxisome proliferator-activated receptor gamma (PPARG, PPARgamma) is associated with good prognosis. Gastroenterology 136(4): 1242-1250. doi: 10.1053/j.gastro.2008.12.048.
72. Park, K.W., D.S. Halperin, and P. Tontonoz. 2008a. Before they were fat: adipocyte progenitors. Cell Metabolism 8(6): 454-457. doi: 10.1016/j.cmet.2008.11.001.
73. Park, K.W., H. Waki, S.P. Choi, K.M. Park, and P. Tontonoz. 2010. The small molecule phenamil is a modulator of adipocyte differentiation and PPARgamma expression. Journal of Lipid Research 51(9): 2775-2784. doi: 10.1194/jlr.M008490.
74. Park, K.W., H. Waki, C.J. Villanueva, L.A. Monticelli, C. Hong, S. Kang, O.A. MacDougald, A.W. Goldrath, and P. Tontonoz. 2008b. Inhibitor of DNA binding 2 is a small molecule-inducible modulator of peroxisome proliferator-activated receptor-gamma expression and adipocyte differentiation. Molecular Endocrinology 22(9): 2038-2048. doi: 10.1210/me.2007-0454.
75. Park, S.J., F. Ahmad, A. Philp, K. Baar, T. Williams, H. Luo, H. Ke, et al. 2012. Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 148(3): 421-433. doi: 10.1016/j.cell.2012.01.017.
76. Pascual, G., A.L. Fong, S. Ogawa, A. Gamliel, A.C. Li, V. Perissi, D.W. Rose, T.M. Willson, M.G. Rosenfeld, and C.K. Glass. 2005. A SUMOylation-dependent pathway mediates transrepression of inflammatory response genes by PPAR-gamma. Nature 437(7059): 759-763. doi: 10.1038/nature03988.
77. Peirce, V., S. Carobbio, and A. Vidal-Puig. 2014. The different shades of fat. Nature 510(7503): 76-83. doi: 10.1038/nature13477.
78. Pi-Sunyer, X. 2003. A clinical view of the obesity problem. Science 299(5608): 859-860. doi: 10.1126/science.1082319299/5608/859.
79. Picard, F., M. Kurtev, N. Chung, A. Topark-Ngarm, T. Senawong, R. Machado De Oliveira, M. Leid, M.W. McBurney, and L. Guarente. 2004. Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gamma. Nature 429(6993): 771-776. doi: 10.1038/nature02583nature02583.
80. Qiu, Y., K.D. Nguyen, J.I. Odegaard, X. Cui, X. Tian, R.M. Locksley, R.D. Palmiter, and A. Chawla. 2014. Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat. Cell 157(6): 1292-1308. doi: 10.1016/j.cell.2014.03.066.
81. Quintanilla, R.A., E. Utreras, and F.A. Cabezas-Opazo. 2014. Role of PPAR gamma in the differentiation and function of neurons. PPAR Research 2014: 768594. doi: 10.1155/2014/768594.
82. Ramkalawan, H., Y.Z. Wang, A. Hurbungs, Y.F. Yang, F.F. Tian, W.B. Zhou, J. Li, H. Yang, B. Xiao, and W. Zhang. 2012. Pioglitazone, PPARgamma agonist, attenuates experimental autoimmune neuritis. Inflammation 35(4): 1338-1347. doi: 10.1007/s10753-012-9447-4.
83. Ramos-Nino, M.E., C.D. MacLean, and B. Littenberg. 2007. Association between cancer prevalence and use of thiazolidinediones: results from the vermont diabetes information system. BMC Medicine 5: 17. doi: 10.1186/1741-7015-5-17.
84. Ricote, M., A.C. Li, T.M. Willson, C.J. Kelly, and C.K. Glass. 1998. The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. Nature 391(6662): 79-82. doi: 10.1038/34178.
85. Saez, E., P. Tontonoz, M.C. Nelson, J.G. Alvarez, U.T. Ming, S.M. Baird, V.A. Thomazy, and R.M. Evans. 1998. Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nature Medicine 4(9): 1058-1061. doi: 10.1038/2042.
86. Sharma, C., A. Pradeep, L. Wong, A. Rana, and B. Rana. 2004. Peroxisome proliferator-activated receptor gamma activation can regulate beta-catenin levels via a proteasome-mediated and adenomatous polyposis coli-independent pathway. Journal of Biological Chemistry 279(34): 35583-35594. doi: 10.1074/jbc.M403143200.
87. Shiau, C.W., C.C. Yang, S.K. Kulp, K.F. Chen, C.S. Chen, J.W. Huang, and C.S. Chen. 2005. Thiazolidenediones mediate apoptosis in prostate cancer cells in part through inhibition of Bcl-xL/Bcl-2 functions independently of PPARgamma. Cancer Research 65(4): 1561-1569. doi: 10.1158/0008-5472.CAN-04-1677.
88. Shoelson, S.E., J. Lee, and M. Yuan. 2003. Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and diet-induced insulin resistance. International Journal of Obesity and Related Metabolic Disorders 27(Suppl 3): S49-S52. doi: 10.1038/sj.ijo.08025010802501.
89. Sikka, S., L. Chen, G. Sethi, and A.P. Kumar. 2012. Targeting PPARgamma signaling cascade for the prevention and treatment of prostate cancer. PPAR Research 2012: 968040. doi: 10.1155/2012/968040.
90. Sims, N.A., and J.H. Gooi. 2008. Bone remodeling: Multiple cellular interactions required for coupling of bone formation and resorption. Seminars in Cell & Developmental Biology 19(5): 444-451. doi: 10.1016/j.semcdb.2008.07.016.
91. Skelhorne-Gross, G., and C.J. Nicol. 2012. The key to unlocking the chemotherapeutic potential of ppargamma ligands: Having the right combination. PPAR Research 2012: 946943. doi: 10.1155/2012/946943.
92. Skelhorne-Gross, G., A.L. Reid, A.J. Apostoli, M.A. Di Lena, R.E. Rubino, N.T. Peterson, M. Schneider, S.K. SenGupta, F.J. Gonzalez, and C.J. Nicol. 2012. Stromal adipocyte PPARgamma protects against breast tumorigenesis. Carcinogenesis 33(7): 1412-1420. doi: 10.1093/carcin/bgs173.
93. Straus, D.S., and C.K. Glass. 2007. Anti-inflammatory actions of PPAR ligands: New insights on cellular and molecular mechanisms. Trends in Immunology 28(12): 551-558. doi: 10.1016/j.it.2007.09.003.
94. Szanto, A., and L. Nagy. 2008. The many faces of PPARgamma: Anti-inflammatory by any means? Immunobiology 213(9-10): 789-803. doi: 10.1016/j.imbio.2008.07.015.
95. Szatmari, I., E. Rajnavolgyi, and L. Nagy. 2006. PPARgamma, a lipid-activated transcription factor as a regulator of dendritic cell function. Annals of the New York Academy of Sciences 1088: 207-218. doi: 10.1196/annals.1366.013.
96. Tontonoz, P., L. Nagy, J.G. Alvarez, V.A. Thomazy, and R.M. Evans. 1998. PPARgamma promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93(2): 241-252.
97. Tontonoz, P., and B.M. Spiegelman. 2008. Fat and beyond: The diverse biology of PPARgamma. Annual Review of Biochemistry 77: 289-312. doi: 10.1146/annurev.biochem.77.061307.091829.
98. Turner, N., G.J. Cooney, E.W. Kraegen, and C.R. Bruce. 2014. Fatty acid metabolism, energy expenditure and insulin resistance in muscle. Journal of Endocrinology 220(2): T61-T79. doi: 10.1530/JOE-13-0397.
99. van Beekum, O., V. Fleskens, and E. Kalkhoven. 2009. Posttranslational modifications of PPAR-gamma: Fine-tuning the metabolic master regulator. Obesity (Silver Spring) 17(2): 213-219. doi: 10.1038/oby.2008.473.
100. van Raalte, D.H., M. Li, P.H. Pritchard, and K.M. Wasan. 2004. Peroxisome proliferator-activated receptor (PPAR)-alpha: A pharmacological target with a promising future. Pharmaceutical Research 21(9): 1531-1538.
101. Vitale, G., S. Zappavigna, M. Marra, A. Dicitore, S. Meschini, M. Condello, G. Arancia, et al. 2012. The PPAR-gamma agonist troglitazone antagonizes survival pathways induced by STAT-3 in recombinant interferon-beta treated pancreatic cancer cells. Biotechnology Advances 30(1): 169-184. doi: 10.1016/j.biotechadv.2011.08.001.
102. Waki, H., K.W. Park, N. Mitro, L. Pei, R. Damoiseaux, D.C. Wilpitz, K. Reue, E. Saez, and P. Tontonoz. 2007. The small molecule harmine is an antidiabetic cell-type-specific regulator of PPARgamma expression. Cell Metabolism 5(5): 357-370. doi: 10.1016/j.cmet.2007.03.010.
103. Waki, H., and P. Tontonoz. 2007. Endocrine functions of adipose tissue. Annual Review of Pathology: Mechanisms of Disease 2: 31-56. doi: 10.1146/annurev.pathol.2.010506.091859.
104. Wang, C.Z., Y. Zhang, X.D. Li, Y. Hu, Z.G. Fang, D.J. Lin, R.Z. Xiao, et al. 2011. PPARgamma agonist suppresses TLR4 expression and TNF-alpha production in LPS stimulated monocyte leukemia cells. Cell Biochemistry and Biophysics 60(3): 167-172. doi: 10.1007/s12013-010-9136-6.
105. Wang, F., S.E. Mullican, J.R. DiSpirito, L.C. Peed, and M.A. Lazar. 2013. Lipoatrophy and severe metabolic disturbance in mice with fat-specific deletion of PPARgamma. The Proceedings of the National Academy USA 110(46): 18656-18661. doi: 10.1073/pnas.1314863110.
106. Wang, L., B. Waltenberger, E.M. Pferschy-Wenzig, M. Blunder, X. Liu, C. Malainer, T. Blazevic, et al. 2014a. Natural product agonists of peroxisome proliferator-activated receptor gamma (PPARgamma): A review. Biochemical Pharmacology. doi: 10.1016/j.bcp.2014.07.018.
107. Wang, S., N. Moustaid-Moussa, L. Chen, H. Mo, A. Shastri, R. Su, P. Bapat, I. Kwun, and C.L. Shen. 2014b. Novel insights of dietary polyphenols and obesity. Journal of Nutritional Biochemistry 25(1): 1-18. doi: 10.1016/j.jnutbio.2013.09.001.
108. Wei, S., L.F. Lin, C.C. Yang, Y.C. Wang, G.D. Chang, H. Chen, and C.S. Chen. 2007. Thiazolidinediones modulate the expression of beta-catenin and other cell-cycle regulatory proteins by targeting the F-box proteins of Skp1-Cul1-F-box protein E3 ubiquitin ligase independently of peroxisome proliferator-activated receptor gamma. Molecular Pharmacology 72(3): 725-733. doi: 10.1124/mol.107.035287.
109. Weisberg, S.P., D. McCann, M. Desai, M. Rosenbaum, R.L. Leibel, and A.W. Ferrante Jr. 2003. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation 112(12): 1796-1808. doi: 10.1172/JCI19246112/12/1796.
110. Wernstedt Asterholm, I., C. Tao, T.S. Morley, Q.A. Wang, F. Delgado-Lopez, Z.V. Wang, and P.E. Scherer. 2014. Adipocyte inflammation is essential for healthy adipose tissue expansion and remodeling. Cell Metabolism 20(1): 103-118. doi: 10.1016/j.cmet.2014.05.005.
111. Xu, H., G.T. Barnes, Q. Yang, G. Tan, D. Yang, C.J. Chou, J. Sole, et al. 2003. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. The Journal of Clinical Investigation 112(12): 1821-1830. doi: 10.1172/JCI19451112/12/1821.
112. Yach, D., D. Stuckler, and K.D. Brownell. 2006. Epidemiologic and economic consequences of the global epidemics of obesity and diabetes. Nature Medicine 12(1): 62-66. doi: 10.1038/nm0106-62.
113. Yan, K.H., C.J. Yao, H.Y. Chang, G.M. Lai, A.L. Cheng, and S.E. Chuang. 2010. The synergistic anticancer effect of troglitazone combined with aspirin causes cell cycle arrest and apoptosis in human lung cancer cells. Molecular Carcinogenesis 49(3): 235-246. doi: 10.1002/mc.20593.
114. Yin, F., S. Wakino, Z. Liu, S. Kim, W.A. Hsueh, A.R. Collins, A.J. Van Herle, and R.E. Law. 2001. Troglitazone inhibits growth of MCF-7 breast carcinoma cells by targeting G1 cell cycle regulators. Biochemical and Biophysical Research Communications 286(5): 916-922. doi: 10.1006/bbrc.2001.5491.
115. Yu, S., K. Matsusue, P. Kashireddy, W.Q. Cao, V. Yeldandi, A.V. Yeldandi, M.S. Rao, F.J. Gonzalez, and J.K. Reddy. 2003. Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression. Journal of Biological Chemistry 278(1): 498-505. doi: 10.1074/jbc.M210062200M210062200.
116. Zander, T., J.A. Kraus, C. Grommes, U. Schlegel, D. Feinstein, T. Klockgether, G. Landreth, J. Koenigsknecht, and M.T. Heneka. 2002. Induction of apoptosis in human and rat glioma by agonists of the nuclear receptor PPARgamma. Journal of Neurochemistry 81(5): 1052-1060.