Table of Contents Author Guidelines Submit a Manuscript
PPAR Research
Volume 2007 (2007), Article ID 97125, 13 pages
http://dx.doi.org/10.1155/2007/97125
Research Article

The Effect of PPARα, PPARδ, PPARγ, and PPARpan Agonists on Body Weight, Body Mass, and Serum Lipid Profiles in Diet-Induced Obese AKR/J Mice

Department of Metabolic Diseases, GlaxoSmithKline Research, Research Triangle Park 27709, NC, USA

Received 18 November 2006; Revised 8 February 2007; Accepted 3 March 2007

Academic Editor: Francine M. Gregoire

Copyright © 2007 W. Wallace Harrington 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. WHO, “Obesity: preventing and managing the global epidemic: report of WHO consultation,” Tech. Rep. 884, WHO Consultation on Obesity, Geneva, Switzerland, 1999.
  2. S. Nammi, S. Koka, K. M. Chinnala, and K. M. Boini, “Obesity: an overview on its current perspectives and treatment options,” Nutrition Journal, vol. 3, p. 3, 2004. View at Publisher · View at Google Scholar · View at PubMed
  3. A. von Eckardstein and G. Assmann, “Prevention of coronary heart disease by raising high-density lipoprotein cholesterol?,” Current Opinion in Lipidology, vol. 11, no. 6, pp. 627–637, 2000. View at Publisher · View at Google Scholar
  4. P. T. James, N. Rigby, and R. Leach, “The obesity epidemic, metabolic syndrome and future prevention strategies,” European Journal of Cardiovascular Prevention and Rehabilitation, vol. 11, no. 1, pp. 3–8, 2004. View at Publisher · View at Google Scholar
  5. E. N. Liberopoulos, D. P. Mikhailidis, and M. S. Elisaf, “Diagnosis and management of the metabolic syndrome in obesity,” Obesity Reviews, vol. 6, no. 4, pp. 283–296, 2005. View at Publisher · View at Google Scholar · View at PubMed
  6. J. Korner and L. J. Aronne, “Pharmacological approaches to weight reduction: therapeutic targets,” Journal of Clinical Endocrinology and Metabolism, vol. 89, no. 6, pp. 2616–2621, 2004. View at Publisher · View at Google Scholar · View at PubMed
  7. D. Cota and S. C. Woods, “The role of the endocannabinoid system in the regulation of energy homeostasis,” Current Opinion in Endocrinology and Diabetes, vol. 12, no. 5, pp. 338–351, 2005. View at Publisher · View at Google Scholar
  8. R. M. Evans, G. D. Barish, and Y.-X. Wang, “PPARs and the complex journey to obesity,” Nature Medicine, vol. 10, no. 4, pp. 355–361, 2004. View at Publisher · View at Google Scholar · View at PubMed
  9. T. M. Willson, P. J. Brown, D. D. Sternbach, and B. R. Henke, “The PPARs: from orphan receptors to drug discovery,” Journal of Medicinal Chemistry, vol. 43, no. 4, pp. 527–550, 2000. View at Publisher · View at Google Scholar
  10. H. E. Xu, M. H. Lambert, and V. G. Montana et al., “Molecular recognition of fatty acids by peroxisome proliferator-activated receptors,” Molecular Cell, vol. 3, no. 3, pp. 397–403, 1999. View at Publisher · View at Google Scholar
  11. M. Guerre-Millo, P. Gervois, and E. Raspé et al., “Peroxisome proliferator-activated receptor α activators improve insulin sensitivity and reduce adiposity,” Journal of Biological Chemistry, vol. 275, no. 22, pp. 16638–16642, 2000. View at Publisher · View at Google Scholar
  12. E. Erol, L. S. Kumar, G. W. Cline, G. I. Shulman, D. P. Kelly, and B. Binas, “Liver fatty acid binding protein is required for high rates of hepatic fatty acid oxidation but not for the action of PPARα in fasting mice,” The FASEB Journal, vol. 18, no. 2, pp. 347–349, 2004.
  13. O. Braissant, F. Foufelle, C. Scotto, M. Dauca, 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
  14. W. R. Oliver, J. L. Shenk, and M. R. Snaith et al., “A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 9, pp. 5306–5311, 2001. View at Publisher · View at Google Scholar · View at PubMed
  15. Y.-X. Wang, C.-H. Lee, and S. Tiep et al., “Peroxisome-proliferator-activated receptor δ activates fat metabolism to prevent obesity,” Cell, vol. 113, no. 2, pp. 159–170, 2003. View at Publisher · View at Google Scholar
  16. Y. X. Wang, C. L. Zhang, and R. T. Yu et al., “Regulation of muscle fiber type and running endurance by PPARδ,” PLoS Biology, vol. 2, no. 10, p. e294, 2004. View at Publisher · View at Google Scholar · View at PubMed
  17. B. M. Spiegelman, “PPAR-γ: adipogenic regulator and thiazolidinedione receptor,” Diabetes, vol. 47, no. 4, pp. 507–514, 1998. View at Publisher · View at Google Scholar
  18. L. Fajas, J.-C. Fruchart, and J. Auwerx, “Transcriptional control of adipogenesis,” Current Opinion in Cell Biology, vol. 10, no. 2, pp. 165–173, 1998. View at Publisher · View at Google Scholar
  19. M. Lehrke and M. A. Lazar, “The many faces of PPARγ,” Cell, vol. 123, no. 6, pp. 993–999, 2005. View at Publisher · View at Google Scholar · View at PubMed
  20. J. E. Cecil, P. Watt, C. N. Palmer, and M. Hetherington, “Energy balance and food intake: the role of PPARγ gene polymorphisms,” Physiology and Behavior, vol. 88, no. 3, pp. 227–233, 2006. View at Publisher · View at Google Scholar · View at PubMed
  21. S. Mudaliar, A. R. Chang, and R. R. Henry, “Thiazolidinediones, peripheral edema, and type 2 diabetes: incidence, pathophysiology, and clinical implications,” Endocrine Practice, vol. 9, no. 5, pp. 406–416, 2003.
  22. 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
  23. M. C. Lewis, J. G. Wilson, D. M. Ignar, and W. R. Oliver, “The effects of PPARα, δ and PPARpan agonist on diet-induced obesity in fat-fed AKR mice,” Diabetes, vol. 53, supplement 2, p. A134, 2004.
  24. B. Pourcet, J.-C. Fruchart, B. Staels, and C. Glineur, “Selective PPAR modulators, dual and pan PPAR agonists: multimodal drugs for the treatment of type 2 diabetes and atherosclerosis,” Expert Opinion on Emerging Drugs, vol. 11, no. 3, pp. 379–401, 2006. View at Publisher · View at Google Scholar · View at PubMed
  25. U. Ramachandran, R. Kumar, and A. Mittal, “Fine tuning of PPAR ligands for type 2 diabetes and metabolic syndrome,” Mini-Reviews in Medicinal Chemistry, vol. 6, no. 5, pp. 563–573, 2006. View at Publisher · View at Google Scholar
  26. P. J. Brown, D. A. Winegar, and K. D. Plunket et al., “A ureido-thioisobutyric acid (GW9578) is a subtype-selective PPARα agonist with potent lipid-lowering activity,” Journal of Medicinal Chemistry, vol. 42, no. 19, pp. 3785–3788, 1999. View at Publisher · View at Google Scholar
  27. B. Yang, K. K. Brown, and L. Chen et al., “Serum adiponectin as a biomarker for in vivo PPARγ activation and PPARγ agonist-induced efficacy on insulin sensitization/lipid lowering in rats,” BMC Pharmacology, vol. 4, no. 1, p. 23, 2004. View at Publisher · View at Google Scholar · View at PubMed
  28. B. R. Henke, S. G. Blanchard, and M. F. Brackeen et al., “N-(2-benzoylphenyl)-L-tyrosine PPARγ agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents,” Journal of Medicinal Chemistry, vol. 41, no. 25, pp. 5020–5036, 1998. View at Publisher · View at Google Scholar · View at PubMed
  29. J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ),” Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995. View at Publisher · View at Google Scholar
  30. J. S. Nichols, D. J. Parks, T. G. Consler, and S. G. Blanchard, “Development of a scintillation proximity assay for peroxisome proliferator-activated receptor γ ligand binding domain,” Analytical Biochemistry, vol. 257, no. 2, pp. 112–119, 1998. View at Publisher · View at Google Scholar · View at PubMed
  31. G. L. Dohm, R. L. Huston, E. W. Askew, and P. C. Weiser, “Effects of exercise on activity of heart and muscle mitochondria,” The American Journal of Physiology, vol. 223, no. 4, pp. 783–787, 1972.
  32. H. R. Scholte, Y. Yu, J. D. Ross, I. I. Oosterkamp, A. M. C. Boonman, and H. F. M. Busch, “Rapid isolation of muscle and heart mitochondria, the lability of oxidative phosphorylation and attempts to stabilize the process in vitro by taurine, carnitine and other compounds,” Molecular and Cellular Biochemistry, vol. 174, no. 1-2, pp. 61–66, 1997. View at Publisher · View at Google Scholar
  33. D. M. Muoio, P. S. MacLean, and D. B. Lang et al., “Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) α knock-out mice: evidence for compensatory regulation by PPARδ,” Journal of Biological Chemistry, vol. 277, no. 29, pp. 26089–26097, 2002. View at Publisher · View at Google Scholar · View at PubMed
  34. P. J. Brown, T. A. Smith-Oliver, and P. S. Charifson et al., “Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library,” Chemistry and Biology, vol. 4, no. 12, pp. 909–918, 1997. View at Publisher · View at Google Scholar
  35. D. C. Dey, R. P. Bronson, J. Dahl, J. P. Carroll, and T. L. Benjamin, “Accelerated development of polyoma tumors and embryonic lethality: different effects of p53 loss on related mouse backgrounds,” Cell Growth & Differentiation, vol. 11, no. 5, pp. 231–237, 2000.
  36. M. L. Sznaidman, C. D. Haffner, and P. R. Maloney et al., “Novel selective small molecule agonists for peroxisome proliferator-activated receptor δ (PPARδ)—synthesis and biological activity,” Bioorganic and Medicinal Chemistry Letters, vol. 13, no. 9, pp. 1517–1521, 2003. View at Publisher · View at Google Scholar
  37. D. B. West, C. N. Boozer, D. L. Moody, and R. L. Atkinson, “Dietary obesity in nine inbred mouse strains,” American Journal of Physiology, vol. 262, no. 6, part 2, pp. R1025–R1032, 1992.
  38. B. K. Smith, D. B. West, and D. A. York, “Carbohydrate versus fat intake: differing patterns of macronutrient selection in two inbred mouse strains,” The American Journal of Physiology, vol. 272, no. 1, part 2, pp. R357–R362, 1997.
  39. V. Prpic, P. M. Watson, I. C. Frampton, M. A. Sabol, G. E. Jezek, and T. W. Gettys, “Adaptive changes in adipocyte gene expression differ in AKR/J and SWR/J mice during diet-induced obesity,” Journal of Nutrition, vol. 132, no. 11, pp. 3325–3332, 2002.
  40. B. Künnecke, P. Verry, A. Bénardeau, and M. von Kienlin, “Quantitative body composition analysis in awake mice and rats by magnetic resonance relaxometry,” Obesity Research, vol. 12, no. 10, pp. 1604–1615, 2004.
  41. E. E. Jobst, P. J. Enriori, P. Sinnayah, and M. A. Cowley, “Hypothalamic regulatory pathways and potential obesity treatment targets,” Endocrine, vol. 29, no. 1, pp. 33–48, 2006. View at Publisher · View at Google Scholar
  42. P. Escher and W. Wahli, “Peroxisome proliferator-activated receptors: insight into multiple cellular functions,” Mutation Research, vol. 448, no. 2, pp. 121–138, 2000. View at Publisher · View at Google Scholar
  43. D. E. Moller and J. P. Berger, “Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation,” International Journal of Obesity, vol. 27, supplement 3, pp. S17–S21, 2003. View at Publisher · View at Google Scholar · View at PubMed
  44. Y. Iwamoto, K. Kosaka, T. Kuzuya, Y. Akanuma, Y. Shigeta, and T. Kaneko, “Effects of troglitazone: a new hypoglycemic agent in patients with NIDDM poorly controlled by diet therapy,” Diabetes Care, vol. 19, no. 2, pp. 151–156, 1996. View at Publisher · View at Google Scholar
  45. M. Narce and J.-P. Poisson, “Novel PPARγ-dependent and independent effects for thiazolidinediones,” Current Opinion in Lipidology, vol. 14, no. 6, pp. 651–652, 2003. View at Publisher · View at Google Scholar · View at PubMed
  46. R. Chakrabarti, R. K. Vikramadithyan, and P. Misra et al., “Ragaglitazar: a novel PPARα & PPARγ agonist with potent lipid-lowering and insulin-sensitizing efficacy in animal models,” British Journal of Pharmacology, vol. 140, no. 3, pp. 527–537, 2003. View at Publisher · View at Google Scholar · View at PubMed
  47. F. Törüner, E. Akbay, and N. Çakir et al., “Effects of PPARγ and PPARα agonists on serum leptin levels in diet-induced obese rats,” Hormone and Metabolic Research, vol. 36, no. 4, pp. 226–230, 2004.
  48. M. Rossmeisl, J. S. Rim, R. A. Koza, and L. P. Kozak, “Variation in type 2 diabetes—related traits in mouse strains susceptible to diet-induced obesity,” Diabetes, vol. 52, no. 8, pp. 1958–1966, 2003. View at Publisher · View at Google Scholar
  49. L. C. Pickavance, C. L. Brand, K. Wassermann, and J. P. H. Wilding, “The dual PPARα/γ agonist, ragaglitazar, improves insulin sensitivity and metabolic profile equally with pioglitazone in diabetic and dietary obese ZDF rats,” British Journal of Pharmacology, vol. 144, no. 3, pp. 308–316, 2005. View at Publisher · View at Google Scholar · View at PubMed
  50. E. H. Koh, M.-S. Kim, and J.-Y. Park et al., “Peroxisome proliferator-activated receptor (PPAR)-α activation prevents diabetes in OLETF rats: comparison with PPAR-γ activation,” Diabetes, vol. 52, no. 9, pp. 2331–2337, 2003. View at Publisher · View at Google Scholar
  51. M. K. Gee, L. Zhang, S. E. Rankin, J. N. Collins, R. F. Kauffman, and J. D. Wagner, “Rosiglitazone treatment improves insulin regulation and dyslipidemia in type 2 diabetic cynomolgus monkeys,” Metabolism, vol. 53, no. 9, pp. 1121–1125, 2004. View at Publisher · View at Google Scholar
  52. I. W. Campbell, “The clinical significance of PPAR γ agonism,” Current Molecular Medicine, vol. 5, no. 3, pp. 349–363, 2005. View at Publisher · View at Google Scholar
  53. C. G. Gegick and M. D. Altheimer, “Thiazolidinediones: comparison of long-term effects on glycemic control and cardiovascular risk factors,” Current Medical Research and Opinion, vol. 20, no. 6, pp. 919–930, 2004. View at Publisher · View at Google Scholar · View at PubMed
  54. M. W. Stolar and R. J. Chilton, “Type 2 diabetes, cardiovascular risk, and the link to insulin resistance,” Clinical Therapeutics, vol. 25, supplement 2, pp. B4–B31, 2003. View at Publisher · View at Google Scholar
  55. H. Duez, J.-C. Fruchart, and B. Staels, “PPARs in inflammation, atherosclerosis and thrombosis,” Journal of Cardiovascular Risk, vol. 8, no. 4, pp. 187–194, 2001. View at Publisher · View at Google Scholar
  56. J. M. Way, W. W. Harrington, and K. K. Brown et al., “Comprehensive messenger ribonucleic acid profiling reveals that peroxisome proliferator-activated receptor γ activation has coordinate effects on gene expression in multiple insulin-sensitive tissues,” Endocrinology, vol. 142, no. 3, pp. 1269–1277, 2001. View at Publisher · View at Google Scholar
  57. S. Hummasti, B. A. Laffitte, and M. A. Watson et al., “Liver X receptors are regulators of adipocyte gene expression but not differentiation: identification of apoD as a direct target,” Journal of Lipid Research, vol. 45, no. 4, pp. 616–625, 2004. View at Publisher · View at Google Scholar · View at PubMed
  58. G. Martin, K. Schoonjans, B. Staels, and J. Auwerx, “PPARγ activators improve glucose homeostasis by stimulating fatty acid uptake in the adipocytes,” Atherosclerosis, vol. 137, supplement 1, pp. S75–S80, 1998. View at Publisher · View at Google Scholar
  59. V. Bocher, I. Pineda-Torra, J.-C. Fruchart, and B. Staels, “PPARS: transcription factors controlling lipid and lipoprotein metabolism,” Annals of the New York Academy of Sciences, vol. 967, pp. 7–18, 2002.
  60. S. Rocchi and J. Auwerx, “Peroxisome proliferator-activated receptor-γ: a versatile metabolic regulator,” Annals of Medicine, vol. 31, no. 5, pp. 342–351, 1999.
  61. 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
  62. F. Zhang, B. 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
  63. A. Fredenrich and P. A. Grimaldi, “PPAR δ: an uncompletely known nuclear receptor,” Diabetes and Metabolism, vol. 31, no. 1, pp. 23–27, 2005. View at Publisher · View at Google Scholar
  64. S. Luquet, J. Lopez-Soriano, and D. Holst et al., “Roles of peroxisome proliferator-activated receptor δ (PPARδ) in the control of fatty acid catabolism. A new target for the treatment of metabolic syndrome,” Biochimie, vol. 86, no. 11, pp. 833–837, 2004. View at Publisher · View at Google Scholar · View at PubMed
  65. H. D. Shin, B. L. Park, and L. H. Kim et al., “Genetic polymorphisms in peroxisome proliferator-activated receptor δ associated with obesity,” Diabetes, vol. 53, no. 3, pp. 847–851, 2004. View at Publisher · View at Google Scholar
  66. M. Muurling, R. P. Mensink, H. Pijl, J. A. Romijn, L. M. Havekes, and P. J. Voshol, “Rosiglitazone improves muscle insulin sensitivity, irrespective of increased triglyceride content, in ob/ob mice,” Metabolism, vol. 52, no. 8, pp. 1078–1083, 2003. View at Publisher · View at Google Scholar
  67. M. D. Leibowitz, C. Fiévet, and N. Hennuyer et al., “Activation of PPARδ alters lipid metabolism in db/db mice,” FEBS Letters, vol. 473, no. 3, pp. 333–336, 2000. View at Publisher · View at Google Scholar
  68. C.-H. Lee, P. Olson, and A. Hevener et al., “PPARδ regulates glucose metabolism and insulin sensitivity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 9, pp. 3444–3449, 2006. View at Publisher · View at Google Scholar · View at PubMed
  69. Y. Fukui, S.-I. Masui, S. Osada, K. Umesono, and K. Motojima, “A new thiazolidinedione, NC-2100, which is a weak PPAR-γ activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice,” Diabetes, vol. 49, no. 5, pp. 759–767, 2000. View at Publisher · View at Google Scholar
  70. N. L. Bodkin, J. Pill, K. Meyer, and B. C. Hansen, “The effects of K-111, a new insulin-sensitizer, on metabolic syndrome in obese prediabetic rhesus monkeys,” Hormone and Metabolic Research, vol. 35, no. 10, pp. 617–624, 2003. View at Publisher · View at Google Scholar · View at PubMed
  71. E. H. Koh, M.-S. Kim, and J.-Y. Park et al., “Peroxisome proliferator-activated receptor (PPAR)-α activation prevents diabetes in OLETF rats: comparison with PPAR-γ activation,” Diabetes, vol. 52, no. 9, pp. 2331–2337, 2003. View at Publisher · View at Google Scholar
  72. P. J. Larsen, P. B. Jensen, and R. V. Sørensen et al., “Differential influences of peroxisome proliferator-activated receptors γ and -α on food intake and energy homeostasis,” Diabetes, vol. 52, no. 9, pp. 2249–2259, 2003. View at Publisher · View at Google Scholar
  73. J. C. Corton, U. Apte, and S. P. Anderson et al., “Mimetics of caloric restriction include agonists of lipid-activated nuclear receptors,” Journal of Biological Chemistry, vol. 279, no. 44, pp. 46204–46212, 2004. View at Publisher · View at Google Scholar · View at PubMed
  74. P. Ferré, “The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity,” Diabetes, vol. 53, supplemnet 1, pp. S43–S50, 2004.
  75. V. Navarro, A. Fernández-Quintela, I. Churruca, and M. P. Portillo, “The body fat-lowering effect conjugated linoleic acid: a comparison between animal and human studies,” Journal of Physiology and Biochemistry, vol. 62, no. 2, pp. 137–147, 2006.
  76. F. Djouadi, J. M. Brandt, C. J. Weinheimer, T. C. Leone, F. J. Gonzalez, and D. P. Kelly, “The role of the peroxisome proliferator-activated receptor α (PPARα) in the control of cardiac lipid metabolism,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 60, no. 5-6, pp. 339–343, 1999. View at Publisher · View at Google Scholar