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PPAR ligands: Potential therapies for metabolic syndrome

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Abstract

Metabolic syndrome (MS), a condition characterized by multiple related clinical disorders including insulin resistance, central obesity, hyperlipidemia, hypertension, and heart disease, is an increasingly prevalent disease in industrialized societies. The intense research interest in the peroxisome proliferator-activated receptors (PPARs), by both the pharmaceutical industry and academia, stems largely from the well-documented therapeutic actions of their synthetic agonists in alleviating several of the maladies associated with MS. This report focuses on the current understanding of the mechanisms of action of PPAR agents and their clinical use in the context of MS.

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References and Recommended Reading

  1. Moller DE, Kaufman KD: Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 2004, Aug 11; [Epub ahead of print]. A comprehensive discussion of the therapeutic approaches for the treatment of MS and their putative mechanisms of action.

  2. Farmer JA: Hypertension and the metabolic syndrome. Curr Cardiol Rep 2004, 6:427–433.

    PubMed  Google Scholar 

  3. Ford ES, Giles WH, Dietz WH: Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002, 287:356–359.

    Article  PubMed  Google Scholar 

  4. Berger J, Moller DE: The mechanisms of action of PPARs. Annu Rev Med 2002, 53:409–435.

    Article  PubMed  CAS  Google Scholar 

  5. Dreyer C, Krey G, Keller H, et al.: Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 1992, 68:879–887.

    Article  PubMed  CAS  Google Scholar 

  6. Spiegelman BM, Hu E, Kim JB, Brun R: PPAR gamma and the control of adipogenesis. Biochimie 1997, 79:111–112.

    Article  PubMed  CAS  Google Scholar 

  7. Kliewer SA, Umesono K, Noonan DJ, et al.: Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 1992, 358:771–774.

    Article  PubMed  CAS  Google Scholar 

  8. Keller H, Dreyer C, Medin J, et al.: Fatty acids and retinoids control lipid metabolism through activation of peroxisome proliferator-activated receptor-retinoid X receptor heterodimers. Proc Natl Acad Sci U S A 1993, 90:2160–2164.

    Article  PubMed  CAS  Google Scholar 

  9. Wahli W, Braissant O, Desvergne B: Peroxisome proliferator activated receptors: transcriptional regulators of adipogenesis, lipid metabolism and more. Chem Biol 1995, 2:261–266.

    Article  PubMed  CAS  Google Scholar 

  10. Wysowski DK, Armstrong G, Governale L: Rapid increase in the use of oral antidiabetic drugs in the United States, 1990–2001. Diabetes Care 2003, 26:1852–1855.

    Article  PubMed  Google Scholar 

  11. Aronoff S, Rosenblatt S, Braithwaite S, et al.: Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized placebo-controlled dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000, 23:1605–1611.

    Article  PubMed  CAS  Google Scholar 

  12. Scherbaum WA, Goke B: Metabolic efficacy and safety of once-daily pioglitazone monotherapy in patients with type 2 diabetes: a double-blind, placebo-controlled study. Horm Metab Res 2002, 34:589–595.

    Article  PubMed  CAS  Google Scholar 

  13. Rosenblatt S, Miskin B, Glazer NB, et al.: The impact of pioglitazone on glycemic control and atherogenic dyslipidemia in patients with type 2 diabetes mellitus. Coron Artery Dis 2001, 12:413–423.

    Article  PubMed  CAS  Google Scholar 

  14. Lebovitz HE, Dole JF, Patwardhan R, et al.: Rosiglitazone monotherapy is effective in patients with type 2 diabetes. J Clin Endocrinol Metab 2001, 86:280–288.

    Article  PubMed  CAS  Google Scholar 

  15. Diani AR,Sawada G,Wyse B,et al.: Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes. Am J Physiol Endocrinol Metab 2004, 286:E116-E122.

    Article  PubMed  CAS  Google Scholar 

  16. Azen SP, Peters RK, Berkowitz K, et al.: TRIPOD (TRoglitazone In the Prevention Of Diabetes): a randomized, placebocontrolled trial of troglitazone in women with prior gestational diabetes mellitus. Control Clin Trials1998,19:217–231.

    Article  Google Scholar 

  17. Gale EA: Lessons from the glitazones: a story of drug development. Lancet 2001, 357:1870–1875.

    Article  PubMed  CAS  Google Scholar 

  18. Yki-Jarvinen H: Thiazolidinediones. N Engl J Med 2004, 351:1106–1118. A recent review of the clinical use of TZDs.

    Article  PubMed  Google Scholar 

  19. Hollenberg NK: Considerations for management of fluid dynamic issues associated with thiazolidinediones. Am J Med 2003, 115(suppl 8A):111S-115S.

    Article  PubMed  CAS  Google Scholar 

  20. Delea TE, Edelsberg JS, Hagiwara M, et al.: Use of thiazolidinediones and risk of heart failure in people with type 2 diabetes: a retrospective cohort study. Diabetes Care 2003, 26:2983–2989.

    Article  PubMed  CAS  Google Scholar 

  21. Lehmann JM, Moore LB, Smith-Oliver TA, et al.: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 1995, 270:12953–12956.

    Article  PubMed  CAS  Google Scholar 

  22. Inzucchi SE, Maggs DG, Spollett GR, et al.: Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 1998, 338:867–872.

    Article  PubMed  CAS  Google Scholar 

  23. Chao L, Marcus-Samuels B, Mason MM, et al.: Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. J Clin Invest 2000, 106:1221–1228.

    PubMed  CAS  Google Scholar 

  24. Rangwala SM, Lazar MA: Peroxisome proliferator-activated receptor gamma in diabetes and metabolism. Trends Pharmacol Sci 2004, 25:331–336. An exhaustive discussion of the regulation of adopokines by PPAR-ã agonists and their effects on insulin sensitivity.

    Article  PubMed  CAS  Google Scholar 

  25. Matsusue K, Haluzik M, Lambert G, et al.: Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 2003, 111:737–747.

    Article  PubMed  CAS  Google Scholar 

  26. Norris AW, Chen L, Fisher SJ, et al.: Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. J Clin Invest 2003, 112:608–618.

    Article  PubMed  CAS  Google Scholar 

  27. Okuno A, Tamemoto H, Tobe K, et al.: Troglitazone increases the number of small adipocytes without the change of white adipose tissue mass in obese Zucker rats. J Clin Invest 1998, 101:1354–1361. A discussion of the effects of troglitazone on white adipose tissue remodeling.

    Article  PubMed  CAS  Google Scholar 

  28. Mayerson AB, Hundal RS, Dufour S, et al.: The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002, 51:797–802.

    Article  PubMed  CAS  Google Scholar 

  29. Kawai T, Takei I, Oguma Y, et al.: Effects of troglitazone on fat distribution in the treatment of male type 2 diabetes. Metabolism 1999, 48:1102–1107.

    Article  PubMed  CAS  Google Scholar 

  30. Laplante M, Sell H, MacNaul KL, et al.: PPAR-gamma activation mediates adipose depot-specific effects on gene expression and lipoprotein lipase activity: mechanisms for modulation of postprandial lipemia and differential adipose accretion. Diabetes 2003, 52:291–299.

    Article  PubMed  CAS  Google Scholar 

  31. Miyazaki Y, Mahankali A, Matsuda M, et al.: Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 2002, 87:2784–2791.

    Article  PubMed  CAS  Google Scholar 

  32. Hegele RA, Cao H, Frankowski C, et al.: PPARG F388L, a transactivation-deficient mutant, in familial partial lipodystrophy. Diabetes 2002, 51:3586–3590.

    Article  PubMed  CAS  Google Scholar 

  33. Savage DB, Tan GD, Acerini CL, et al.: Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes 2003, 52:910–917.

    Article  PubMed  CAS  Google Scholar 

  34. Berg AH, Combs TP, Du X, et al.: The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 2001, 7:947–953.

    Article  PubMed  CAS  Google Scholar 

  35. Yamauchi T, Kamon J, Waki H, et al.: The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001, 7:941–946.

    Article  PubMed  CAS  Google Scholar 

  36. Combs TP, Wagner JA, Berger J, et al.: Induction of adipocyte complement-related protein of 30 kilodaltons by PPARgamma agonists: a potential mechanism of insulin sensitization. Endocrinology 2002, 143:998–1007.

    Article  PubMed  CAS  Google Scholar 

  37. Bajaj M, Suraamornkul S, Piper P, et al.: Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazonetreated type 2 diabetic patients. J Clin Endocrinol Metab 2004, 89:200–206.

    Article  PubMed  CAS  Google Scholar 

  38. Gottschling-Zeller H, Rohrig K, Hauner H: Troglitazone reduces plasminogen activator inhibitor-1 expression and secretion in cultured human adipocytes. Diabetologia 2000, 43:377–383.

    Article  PubMed  CAS  Google Scholar 

  39. Harte AL, McTernan PG, McTernan CL, et al.: Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes. Diabetes Obes Metab 2003, 5:302–310.

    Article  PubMed  CAS  Google Scholar 

  40. Sigrist S, Bedoucha M, Boelsterli UA: Down-regulation by troglitazone of hepatic tumor necrosis factor-alpha and interleukin-6 mRNA expression in a murine model of non-insulin-dependent diabetes. Biochem Pharmacol 2000, 60:67–75.

    Article  PubMed  CAS  Google Scholar 

  41. Masuzaki H, Paterson J, Shinyama H, et al.: A transgenic model of visceral obesity and the metabolic syndrome. Science 2001, 294:2166–2170.

    Article  PubMed  CAS  Google Scholar 

  42. Walker BR, Seckl JR: 11beta-hydroxysteroid dehydrogenase type 1 as a novel therapeutic target in metabolic and neurodegenerative disease. Expert Opin Ther Targets 2003, 7:771–783.

    Article  PubMed  CAS  Google Scholar 

  43. Berger J, Tanen M, Elbrecht A, et al.: Peroxisome proliferatoractivated receptor-gamma ligands inhibit adipocyte 11beta - hydroxysteroid dehydrogenase type 1 expression and activity. J Biol Chem 2001, 276:12629–12635.

    Article  PubMed  CAS  Google Scholar 

  44. Plutzky J: Emerging concepts in metabolic abnormalities associated with coronary artery disease. Curr Opin Cardiol 2000, 15:416–421.

    Article  PubMed  CAS  Google Scholar 

  45. Verges B: Clinical interest of PPARs ligands. Diabetes Metab 2004, 30:7–12.

    Article  PubMed  CAS  Google Scholar 

  46. Reddy JK, Hashimoto T: Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr 2001, 21:193–230.

    Article  PubMed  CAS  Google Scholar 

  47. Staels B, Dallongeville J, Auwerx J, et al.: Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation 1998, 98:2088–2093.

    PubMed  CAS  Google Scholar 

  48. Fruchart JC: Peroxisome proliferator-activated receptoralpha activation and high-density lipoprotein metabolism. Am J Cardiol 2001, 88:24N-29N.

    Article  PubMed  CAS  Google Scholar 

  49. Manninen V, Elo MO, Frick MH, et al.: Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study. JAMA 1988, 260:641–651.

    Article  PubMed  CAS  Google Scholar 

  50. Chang JT, Staffa JA, Parks M, Green L: Rhabdomyolysis with HMG-CoA reductase inhibitors and gemfibrozil combination therapy. Pharmacoepidemiol Drug Saf 2004, 13:417–426.

    Article  PubMed  CAS  Google Scholar 

  51. Oliver WR Jr, Shenk JL, Snaith MR, et al.: A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci U S A 2001, 98:5306–5311.

    Article  PubMed  CAS  Google Scholar 

  52. Tanaka T, Yamamoto J, Iwasaki S, et al.: Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc Natl Acad Sci U S A 2003, 100:15924–15929.

    Article  PubMed  CAS  Google Scholar 

  53. Wang YX, Lee CH, Tiep S, et al.: Peroxisome-proliferatoractivated receptor delta activates fat metabolism to prevent obesity. Cell 2003, 113:159–170.

    Article  PubMed  CAS  Google Scholar 

  54. Wang YX, Zhang CL, Yu RT, et al.: Regulation of muscle fiber type and running endurance by PPARdelta. PLoS Biol 2004, 2:1532–1539.

    CAS  Google Scholar 

  55. Tan NS, Michalik L, Noy N, et al.: Critical roles of PPAR beta/ delta in keratinocyte response to inflammation. Genes Dev 2001, 15:3263–3277.

    Article  PubMed  CAS  Google Scholar 

  56. Harman FS, Nicol CJ, Marin HE, et al.: Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. Nat Med 2004, 10:481–483.

    Article  PubMed  CAS  Google Scholar 

  57. Park BH, Vogelstein B, Kinzler KW: Genetic disruption of PPARdelta decreases the tumorigenicity of human colon cancer cells. Proc Natl Acad Sci U S A 2001, 98:2598–2603.

    Article  PubMed  CAS  Google Scholar 

  58. Linton MF, Fazio S: Re-emergence of fibrates in the management of dyslipidemia and cardiovascular risk. Curr Atheroscler Rep 2000, 2:29–35.

    PubMed  CAS  Google Scholar 

  59. Rubins HB, Robins SJ, Collins D, et al.: Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Intern Med 2002, 162:2597–2604.

    Article  PubMed  CAS  Google Scholar 

  60. Steiner G: Treating lipid abnormalities in patients with type 2 diabetes mellitus. Am J Cardiol 2001, 88:37N-40N.

    Article  PubMed  CAS  Google Scholar 

  61. Hsueh WA, Bruemmer D: Peroxisome proliferator-activated receptor gamma: implications for cardiovascular disease. Hypertension 2004, 43:297–305.

    Article  PubMed  CAS  Google Scholar 

  62. Minamikawa J, Tanaka S, Yamauchi M, et al.: Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab 1998, 83:1818–1820.

    Article  PubMed  CAS  Google Scholar 

  63. Libby P, Ridker PM, Maseri A: Inflammation and atherosclerosis. Circulation 2002, 105:1135–1143.

    Article  PubMed  CAS  Google Scholar 

  64. Marx N, Froehlich J, Siam L, et al.: Antidiabetic PPAR gammaactivator rosiglitazone reduces MMP-9 serum levels in type 2 diabetic patients with coronary artery disease. Arterioscler Thromb Vasc Biol 2003, 23:283–288.

    Article  PubMed  CAS  Google Scholar 

  65. Saad MF, Greco S, Osei K, et al.: Ragaglitazar improves glycemic control and lipid profile in type 2 diabetic subjects: a 12-week, double-blind, placebo-controlled dose-ranging study with an open pioglitazone arm. Diabetes Care 2004, 27:1324–1329.

    Article  PubMed  CAS  Google Scholar 

  66. Sternbach DD, Rafferty S, Cadilla R, et al. Synthesis and crystal structure of a PPARpan agonist that delivers glycemic control and improved lipid profiles without weight gain. Paper presented at the 28th International Symposium on Medicinal Chemistry. Copenhagen, Denmark; August 15–19, 2004.

  67. Berger JP, Petro AE, Macnaul KL, et al.: Distinct properties and advantages of a novel peroxisome proliferator-activated receptor [gamma] selective modulator. Mol Endocrinol 2003, 17:662–676. A seminal finding demonstrating that a SPPARãM, nTZDpa, had comparable efficacy and improved tolerability versus PPAR-ã full agonists in preclinical species.

    Article  PubMed  CAS  Google Scholar 

  68. Arakawa K, Ishihara T, Aoto M, et al.: An antidiabetic thiazolidinedione induces eccentric cardiac hypertrophy by cardiac volume overload in rats. Clin Exp Pharmacol Physiol 2004, 31:8–13.

    Article  PubMed  CAS  Google Scholar 

  69. Acton JJ III, Black RM, Jones AB, et al.: Benzoyl 2-methyl indoles as selective PPARgamma modulators. Bioorg Med Chem Lett 2005, 15:357–362.

    Article  PubMed  CAS  Google Scholar 

  70. Minoura H, Takeshita S, Ita M, et al.: Pharmacological characteristics of a novel nonthiazolidinedione insulin sensitizer, FK614. Eur J Pharmacol 2004, 494:273–281.

    Article  PubMed  CAS  Google Scholar 

  71. Benson SC, Pershadsingh HA, Ho CI, et al.: Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension 2004, 43:993–1002.

    Article  PubMed  CAS  Google Scholar 

  72. Pershadsingh HA, Kurtz TW: Insulin-sensitizing effects of telmisartan: implications for treating insulin-resistant hypertension and cardiovascular disease. Diabetes Care 2004, 27:1015.

    Article  PubMed  Google Scholar 

  73. Kersey K, Floren LC, Pendleton B, et al.: T0903131, a selective modulator of PPAR-gamma activity, increases adiponectin levels in healthy subjects. Presented at the 64th International ADA Scientific Sessions. Orlando, FL; June 4–8, 2004.

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Akiyama, T.E., Meinke, P.T. & Berger, J.P. PPAR ligands: Potential therapies for metabolic syndrome. Curr Diab Rep 5, 45–52 (2005). https://doi.org/10.1007/s11892-005-0067-3

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