Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2007, Article ID 32696, 7 pages
http://dx.doi.org/10.1155/2007/32696
Review Article

Selective Modulators of PPAR-γ Activity: Molecular Aspects Related to Obesity and Side-Effects

Department of Biology, Metabolex Inc., 3876 Bay Center Place, Hayward 94545, CA, USA

Received 3 October 2006; Revised 21 November 2006; Accepted 22 November 2006

Academic Editor: Sander Kersten

Copyright © 2007 Fang Zhang 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. S. A. Kliewer, S. S. Sundseth, and S. A. Jones et al., “Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors α and γ,” Proceedings of the National Academy of Sciences of the United States of America, vol. 94, no. 9, pp. 4318–4323, 1997. View at Publisher · View at Google Scholar
  2. T. M. Willson, J. E. Cobb, and D. J. Cowan et al., “The structure-activity relationship between peroxisome proliferator-activated receptor γ agonism and the antihyperglycemic activity of thiazolidinediones,” Journal of Medicinal Chemistry, vol. 39, no. 3, pp. 665–668, 1996. View at Publisher · View at Google Scholar · View at PubMed
  3. M. Gurnell, D. B. Savage, V. K. K. Chatterjee, and S. O'Rahilly, “The metabolic syndrome: peroxisome proliferator-activated receptor γ and its therapeutic modulation,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 6, pp. 2412–2421, 2003. View at Publisher · View at Google Scholar
  4. 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
  5. R. W. Nesto, D. Bell, and R. O. Bonow et al., “Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association,” Circulation, vol. 108, no. 23, pp. 2941–2948, 2003. View at Publisher · View at Google Scholar · View at PubMed
  6. F. Zhang, B. E. Lavan, and F. M. Gregoire, “Peroxisome proliferator-activated receptors as attractive antiobesity targets,” Drug News and Perspectives, vol. 17, no. 10, pp. 661–669, 2004. View at Publisher · View at Google Scholar
  7. T. M. Larsen, S. Toubro, and A. Astrup, “PPARγ agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?,” International Journal of Obesity, vol. 27, no. 2, pp. 147–161, 2003. View at Publisher · View at Google Scholar · View at PubMed
  8. R. W. Nesto, D. Bell, and R. O. Bonow et al., “Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association,” Diabetes Care, vol. 27, no. 1, pp. 256–263, 2004. View at Publisher · View at Google Scholar
  9. Z. Hussein, J. M. Wentworth, A. J. Nankervis, J. Proietto, and P. G. Colman, “Effectiveness and side effects of thiazolidinediones for type 2 diabetes: real-life experience from a tertiary hospital,” Medical Journal of Australia, vol. 181, no. 10, pp. 536–539, 2004.
  10. E. H. Ryan Jr., D. P. Han, and R. C. Ramsay et al., “Diabetic macular edema associated with glitazone use,” Retina, vol. 26, no. 5, pp. 562–570, 2006. View at Publisher · View at Google Scholar
  11. J. M. Olefsky, “Treatment of insulin resistance with peroxisome proliferator-activated receptor γ agonists,” Journal of Clinical Investigation, vol. 106, no. 4, pp. 467–472, 2000.
  12. C. Knouff and J. Auwerx, “Peroxisome proliferator-activated receptor-γ calls for activation in moderation: lessons from genetics and pharmacology,” Endocrine Reviews, vol. 25, no. 6, pp. 899–918, 2004. View at Publisher · View at Google Scholar · View at PubMed
  13. R. T. Nolte, G. B. Wisely, and S. Westin et al., “Ligand binding and co-activator assembly of the peroxisome proliferator-activated receptor-γ,” Nature, vol. 395, no. 6698, pp. 137–143, 1998. View at Publisher · View at Google Scholar · View at PubMed
  14. E. Burgermeister, A. Schnoebelen, and A. Flament et al., “A novel partial agonist of peroxisome proliferator-activated receptor-γ (PPARγ) recruits PPARγ-coactivator-1α, prevents triglyceride accumulation, and potentiates insulin signaling in vitro,” Molecular Endocrinology, vol. 20, no. 4, pp. 809–830, 2006. View at Publisher · View at Google Scholar · View at PubMed
  15. J. L. Oberfield, J. L. Collins, and C. P. Holmes et al., “A peroxisome proliferator-activated receptor γ ligand inhibits adipocyte differentiation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 11, pp. 6102–6106, 1999. View at Publisher · View at Google Scholar
  16. A. R. Miller and G. J. Etgen, “Novel peroxisome proliferator-activated receptor ligands for type 2 diabetes and the metabolic syndrome,” Expert Opinion on Investigational Drugs, vol. 12, no. 9, pp. 1489–1500, 2003. View at Publisher · View at Google Scholar · View at PubMed
  17. T.-A. Cock, S. M. Houten, and J. Auwerx, “Peroxisome proliferator-activated receptor-γ: too much of a good thing causes harm,” EMBO Reports, vol. 5, no. 2, pp. 142–147, 2004. View at Publisher · View at Google Scholar · View at PubMed
  18. S. M. Rangwala and M. A. Lazar, “The dawn of the SPPARMs?,” Science's Signal Transduction Knowledge Environment, vol. 2002, no. 121, p. Pe9, 2002. View at Publisher · View at Google Scholar · View at PubMed
  19. F. Picard, M. Géhin, and J.-S. Annicotte et al., “SRC-1 and TIF2 control energy balance between white and brown adipose tissues,” Cell, vol. 111, no. 7, pp. 931–941, 2002. View at Publisher · View at Google Scholar
  20. S. Rocchi, F. Picard, and J. Vamecq et al., “A unique PPARγ ligand with potent insulin-sensitizing yet weak adipogenic activity,” Molecular Cell, vol. 8, no. 4, pp. 737–747, 2001. View at Publisher · View at Google Scholar
  21. J. P. Berger, A. E. Petro, and K. L. Macnaul et al., “Distinct properties and advantages of a novel peroxisome proliferator-activated protein γ selective modulator,” Molecular Endocrinology, vol. 17, no. 4, pp. 662–676, 2003. View at Publisher · View at Google Scholar · View at PubMed
  22. A. Elbrecht, Y. Chen, and A. Adams et al., “L-764406 is a partial agonist of human peroxisome proliferator-activated receptor γ. The role of Cys313 in ligand binding,” Journal of Biological Chemistry, vol. 274, no. 12, pp. 7913–7922, 1999. View at Publisher · View at Google Scholar
  23. E. Kurosaki, R. Nakano, and K. Momose et al., “Hypoglycemic agent YM440 suppresses hepatic glucose output via gluconeogenesis by reducing glucose-6-phosphatase activity in obese Zucker rats,” European Journal of Pharmacology, vol. 468, no. 2, pp. 151–158, 2003. View at Publisher · View at Google Scholar
  24. A. Shimaya, E. Kurosaki, R. Nakano, R. Hirayama, M. Shibasaki, and H. Shikama, “The novel hypoglycemic agent YM440 normalizes hyperglycemia without changing body fat weight in diabetic db/db mice,” Metabolism, vol. 49, no. 3, pp. 411–417, 2000. View at Publisher · View at Google Scholar
  25. R. Nakano, E. Kurosaki, A. Shimaya, and M. Shibasaki, “The novel hypoglycemic agent YM440 improves hepatic insulin resistance in obese Zucker fatty rats,” Journal of Pharmacological Sciences, vol. 101, no. 4, pp. 311–317, 2006. View at Publisher · View at Google Scholar
  26. R. Chakrabarti, R. K. Vikramadithyan, P. Misra, J. Suresh, and R. Rajagopalan, “Balaglitazone, a quinazalone analogue of thiazolidione shows excellent antidiabetic and hypolipidemic potential with less adipogenic activity,” Diabetes, vol. 52, supplement 1, p. 601-P, 2003.
  27. D. Koev, C. Ionescu-Trgoviste, and A. Rosenthal et al., “Balaglitazone, a new thiazolidinedione, improves glucose and lipid control in patients with type 2 diabetes,” Diabetes, vol. 52, supplement 1, p. 530-P, 2003.
  28. E. M. Wulff, K. E. Pedersen, and P. Sauerberg, “Balaglitazone a new partial PPAR γ agonist has a better cardio vascular safety profile and glycemic control compared with the full PPAR γ agonist rosiglitazone,” Diabetes, vol. 52, supplement 1, p. 594P, 2003.
  29. M. J. Reginato, S. T. Bailey, and S. L. Krakow et al., “A potent antidiabetic thiazolidinedione with unique peroxisome proliferator-activated receptor γ-activating properties,” Journal of Biological Chemistry, vol. 273, no. 49, pp. 32679–32684, 1998. View at Publisher · View at Google Scholar
  30. L. S. Liu, H. Tanaka, S. Ishii, and J. Eckel, “The new antidiabetic drug MCC-555 acutely sensitizes insulin signaling in isolated cardiomyocytes,” Endocrinology, vol. 139, no. 11, pp. 4531–4539, 1998. View at Publisher · View at Google Scholar
  31. R. Upton, P. S. Widdowson, S. Ishii, H. Tanaka, and G. Williams, “Improved metabolic status and insulin sensitivity in obese fatty (fa/fa) Zucker rats and Zucker Diabetic Fatty (ZDF) rats treated with the thiazolidinedione, MCC-555,” British Journal of Pharmacology, vol. 125, no. 8, pp. 1708–1714, 1998. View at Publisher · View at Google Scholar · View at PubMed
  32. D. Dey, S. Medicherla, and P. Neogi et al., “A novel peroxisome proliferator-activated gamma (PPARγ) agonist, CLX-0921, has potent antihyperglycemic activity with low adipogenic potential,” Metabolism, vol. 52, no. 8, pp. 1012–1018, 2003. View at Publisher · View at Google Scholar
  33. J. J. Acton III, R. M. Black, and A. B. Jones et al., “Benzoyl 2-methyl indoles as selective PPARγ modulators,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 2, pp. 357–362, 2005. View at Publisher · View at Google Scholar · View at PubMed
  34. K. Liu, R. M. Black, and J. J. Acton III et al., “Selective PPARγ modulators with improved pharmacological profiles,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 10, pp. 2437–2440, 2005. View at Publisher · View at Google Scholar · View at PubMed
  35. J. F. Dropinski, T. Akiyama, and M. Einstein et al., “Synthesis and biological activities of novel aryl indole-2-carboxylic acid analogs as PPARγ partial agonists,” Bioorganic and Medicinal Chemistry Letters, vol. 15, no. 22, pp. 5035–5038, 2005. View at Publisher · View at Google Scholar · View at PubMed
  36. T. Fujimura, C. Kimura, and T. Oe et al., “A selective peroxisome proliferator-activated receptor γ modulator with distinct fat cell regulation properties,” Journal of Pharmacology and Experimental Therapeutics, vol. 318, no. 2, pp. 863–871, 2006. View at Publisher · View at Google Scholar · View at PubMed
  37. T. Fujimura, H. Sakuma, and S. Konishi et al., “FK614, a novel peroxisome proliferator-activated receptor γ modulator, induces differential transactivation through a unique ligand-specific interaction with transcriptional coactivators,” Journal of Pharmacological Sciences, vol. 99, no. 4, pp. 342–352, 2005. View at Publisher · View at Google Scholar
  38. H. Minoura, S. Takeshita, and T. Yamamoto et al., “Ameliorating effect of FK614, a novel nonthiazolidinedione peroxisome proliferator-activated receptor γ agonist, on insulin resistance in Zucker fatty rat,” European Journal of Pharmacology, vol. 519, no. 1-2, pp. 182–190, 2005. View at Publisher · View at Google Scholar · View at PubMed
  39. H. Minoura, S. Takeshita, and M. Ita et al., “Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, FK614,” European Journal of Pharmacology, vol. 494, no. 2-3, pp. 273–281, 2004. View at Publisher · View at Google Scholar · View at PubMed
  40. K. R. Kim, J. H. Lee, and S. J. Kim et al., “KR-62980: a novel peroxisome proliferator-activated receptor γ agonist with weak adipogenic effects,” Biochemical Pharmacology, vol. 72, no. 4, pp. 446–454, 2006. View at Publisher · View at Google Scholar · View at PubMed
  41. S. C. Benson, H. A. Pershadsingh, and C. I. Ho et al., “Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activity,” Hypertension, vol. 43, no. 5, pp. 993–1002, 2004. View at Publisher · View at Google Scholar · View at PubMed
  42. M. Schupp, M. Clemenz, and R. Gineste et al., “Molecular characterization of new selective peroxisome proliferator-activated receptor γ modulators with angiotensin receptor blocking activity,” Diabetes, vol. 54, no. 12, pp. 3442–3452, 2005. View at Publisher · View at Google Scholar
  43. M. Schupp, L. D. Lee, and N. Frost et al., “Regulation of peroxisome proliferator-activated receptor γ activity by losartan metabolites,” Hypertension, vol. 47, no. 3, pp. 586–589, 2006. View at Publisher · View at Google Scholar · View at PubMed
  44. K. Araki, T. Masaki, I. Katsuragi, K. Tanaka, T. Kakuma, and H. Yoshimatsu, “Telmisartan prevents obesity and increases the expression of uncoupling protein 1 in diet-induced obese mice,” Hypertension, vol. 48, no. 1, pp. 51–57, 2006. View at Publisher · View at Google Scholar · View at PubMed
  45. T. Allen, F. Zhang, and S. A. Moodie et al., “Halofenate is a selective peroxisome proliferator-activated receptor γ modulator with antidiabetic activity,” Diabetes, vol. 55, no. 9, pp. 2523–2533, 2006. View at Publisher · View at Google Scholar · View at PubMed
  46. F. Zhang, E. Clemens, and F. M. Gregoire et al., “Metaglidasen, a selective PPARγ modulator (SPPARγM) with anti-diabetic and hypo-lipidemic activity in multiple diabetic and insulin-resistant rat models,” in Conference on Diabetes Mellitus and the Control of Cellular Energy Metabolism, Keystone Symposia, Vancouver, BC, Canada, January 2006, abstract no. 342a .
  47. F. Zhang, E. L. Clemens, and F. M. Gregoire et al., “Metaglidasen, a novel selective peroxisome proliferator-activated receptor-γ modulator, preserves pancreatic islet structure and function in db/db mice,” Diabetes, vol. 55, p. 1396-P, 2006.
  48. R. S. Savkur and A. R. Miller, “Investigational PPAR-γ agonists for the treatment of type 2 diabetes,” Expert Opinion on Investigational Drugs, vol. 15, no. 7, pp. 763–778, 2006. View at Publisher · View at Google Scholar · View at PubMed
  49. Y. Li, Z. Wang, and A. Motani et al., “T0903131 (T131): A selective modulator of PPARγ,” Diabetes, vol. 53, supplement 2, p. A157, 2004.
  50. B. L. Balint and L. Nagy, “Selective modulators of PPAR activity as new therapeutic tools in metabolic diseases,” Endocrine, Metabolic and Immune Disorders - Drug Targets, vol. 6, no. 1, pp. 33–43, 2006.
  51. Y. Guan, C. Hao, and D. R. Cha et al., “Thiazolidinediones expand body fluid volume through PPARγ stimulation of ENaC-mediated renal salt absorption,” Nature Medicine, vol. 11, no. 8, pp. 861–866, 2005. View at Publisher · View at Google Scholar · View at PubMed
  52. H. Zhang, A. Zhang, D. E. Kohan, R. D. Nelson, F. J. Gonzalez, and T. Yang, “Collecting duct-specific deletion of peroxisome proliferator-activated receptor γ blocks thiazolidinedione-induced fluid retention,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 26, pp. 9406–9411, 2005. View at Publisher · View at Google Scholar · View at PubMed
  53. J. Rosenstock, F. Flores-Lozano, S. Schartz, G. Gonzalez-Galvez, and D. Karpf, “MBX-102: a novel non-TZD insulin sensitizer that improves glycemic control without causing edema or weight gain in patients with type 2 diabetes (T2DM) on concomitant insulin therapy,” Diabetes, vol. 54, supplement 1, p. A11, 2005.
  54. H. A. Pershadsingh, “Treating the metabolic syndrome using angiotensin receptor antagonists that selectively modulate peroxisome proliferator-activated receptor-γ,” International Journal of Biochemistry and Cell Biology, vol. 38, no. 5-6, pp. 766–781, 2006. View at Publisher · View at Google Scholar · View at PubMed
  55. C. Di Filippo, E. Lampa, and E. Tufariello et al., “Effects of irbesartan on the growth and differentiation of adipocytes in obese Zucker rats,” Obesity Research, vol. 13, no. 11, pp. 1909–1914, 2005.
  56. J. Janke, M. Schupp, and S. Engeli et al., “Angiotensin type 1 receptor antagonists induce human in-vitro adipogenesis through peroxisome proliferator-activated receptor-γ activation,” Journal of Hypertension, vol. 24, no. 9, pp. 1809–1816, 2006. View at Publisher · View at Google Scholar · View at PubMed
  57. M. C. Michel, H. Bohner, J. Köster, R. Schäfers, and U. Heemann, “Safety of telmisartan in patients with arterial hypertension: an open-label observational study,” Drug Safety, vol. 27, no. 5, pp. 335–344, 2004. View at Publisher · View at Google Scholar
  58. C. Vitale, G. Mercuro, and C. Castiglioni et al., “Metabolic effect of telmisartan and losartan in hypertensive patients with metabolic syndrome,” Cardiovascular Diabetology, vol. 4, Article ID 6, 2005. View at Publisher · View at Google Scholar · View at PubMed
  59. G. Derosa, P. D. Ragonesi, A. Mugellini, L. Ciccarelli, and R. Fogari, “Effects of telmisartan compared with eprosartan on blood pressure control, glucose metabolism and lipid profile in hypertensive, type 2 diabetic patients: a randomized, double-blind, placebo-controlled 12-month study,” Hypertension Research, vol. 27, no. 7, pp. 457–464, 2004. View at Publisher · View at Google Scholar
  60. Y. Miura, N. Yamamoto, and S. Tsunekawa et al., “Replacement of valsartan and candesartan by telmisartan in hypertensive patients with type 2 diabetes: metabolic and antiatherogenic consequences,” Diabetes Care, vol. 28, no. 3, pp. 757–758, 2005. View at Publisher · View at Google Scholar
  61. R. A. Benndorf, T. Rudolph, and D. Appel et al., “Telmisartan improves insulin sensitivity in nondiabetic patients with essential hypertension,” Metabolism, vol. 55, no. 9, pp. 1159–1164, 2006. View at Publisher · View at Google Scholar · View at PubMed