The relationship of lipid imbalance and chronic inflammation mediated by PPAR


Authors: Tomáš Čavojský;  František Bilka;  Ingrid Pauliková
Published in: Čes. slov. Farm., 2016; 65, 3-9
Category: Review Articles

Overview

Obesity is a serious metabolic disease that threatens patients with increasing incidence of the metabolic, cardiovascular, cancer1–3) and other associated, especially autoimmune diseases. It increases significantly the morbidity and mortality of patients and reduces quality of their life.

The imbalance between lipolysis and lipogenesis results in a number of metabolic related disorders at the different regulatory levels of transcription, translation, and/or activity of enzymes. One of the extensively studied areas in regulating lipogenesis, often accompanied by inflammation, is a peroxisome proliferator activated receptors (PPARs), especially its isomer PPAR-γ. PPAR-γ is a ligand-activated transcription factor belonging to the family of nuclear receptors. It is mostly presented in differentiated macrophages and adipose tissue5, 6). It has an important function of adipocyte differentiation and inflammation management in terms of gene expression inhibition of pro-inflammatory cytokines. PPAR-γ inhibition of inflammatory cytokines such as TNF-α may present the molecular mechanism of lipid disorders, thus contributing to the pathogenesis of various diseases, e.g. inflammation, insulin resistance and atherosclerosis, for which the lipid metabolism disorders are a common feature. Under the action of specific agonists, PPAR-γ alter the release of signal molecules from adipose tissue, which has far-reaching metabolic consequences in other tissues. It plays an important role in the inhibition of inflammation and the development of insulin resistance.

Key words:
obesityinflammationPPAR-γcytokines


Sources

1. Berg A. H. Adipose tissue, inflammation, and cardiovascular disease. Circ Res. 2005; 96, 939–949.

2. Wellen K. E. Inflammation, stress, and diabetes. J Clin Invest. 2005; 115: 1111–1119.

3. Hossain P., Kawar B., El Nahas M. Obesity and diabetes in the developing world – a growing challenge. N Engl J Med. 2007; 356, 213–215.

4. Czernichow S., Kengne A. P., Stamatakis E., Hamer M.,  Batty G. D. Body mass index, waist circumference and waist-hip ratio: which is the better discriminator of cardiovascular disease mortality risk?: evidence from an individual-participant meta-analysis of 82 864 participants from nine cohort studies. Obes Rev. 2011; 12, 680–687.

5. Chen F. Biochem. Biophys. Res. Commun. 1993; 196, 671–677.

6. Braissant O. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-alpha, -beta, and -gamma in the adult rat Endocrinology 1996; 137, 354–366.

7. Finucane M. M., Stevens G. A., Cowan M. J. Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Body Mass Index). National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9·1 million participants. Lancet 2011; 377, 557–567.

8. Controlling the global obesity epidemic http://www. who.int/nutrition/topics/obesity/en/ (25. 1. 16).

9. Jernas M., Palming J., Sjoholm K. Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression. The FASEB Journal 2006; 20(9), 1540–1542.

10. Farrel G. C., Larter C. Z. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatologyno. 2006; 43(Suppl 1), 99–112.

11. Zimmet P., Magliano D., Matsuzawa Y., Alberti G., Shaw, J. The metabolic syndrome: a global public health problem and a new definition. J. Atheroscler. Thromb. 2005; 12, 295–300.

12. Grundy S. M., Brewer Jr. H. B., Cleeman J. I., Smith Jr. S. C., Lenfant C. Definition of metabolic syndrome: report of the National Heart, Lung, and Blood Institute/American Heart Association conference on scientific issues related to definition. Circulation 2004; 109, 433–438.

13. Ahima R. S., Flier J. S. Adipose tissue as an endocrine organ. Trends Endocrinol Metab. 2000; 11, 327–332. 

14. Fruhbeck G., Gomez-Ambrosi J., Muruzabal F. J., Burrell M. A. The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab. 2001; 280, E827—E847.

15. Klaus S. Adipose tissue as a regulator of energy balance. Curr Drug Targets. 2004; 5, 241–250.

16. Frayn K. N., Karpe F., Fielding B. A., Macdonald I. A., Coppack S. W. Integrative physiology of human adipose tissue. Int J Obes Relat Metab Disord. 2003; 27, 875–888.

17. Fain J. N., Madan A. K., Hiler M. L., Cheema P., Bahouth S. W. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology 2004; 145, 2273–2282.

18. Rosen E. D., Spiegelman B. M. Molecular regulation of adipogenesis. Annu Rev Cell Dev Biol. 2000; 16, 145–171.

19. Rosen E. D., Macdougald O. A. Adipocyte differentiation from the inside out. Nat Rev Mol Cell Biol. 2006; 7, 885–896.

20. Charriere G., Cousin B., Arnaud E., Andre M., Bacou F., Penicaud L., Casteilla L. Preadipocyte conversion to macrophage. Evidence of plasticity. J Biol Chem. 2003; 278, 9850–9855.

21. Cousin B., Munoz O., Andre M., Fontanilles A. M., Dani C., Cousin J. L., Laharrague P., Casteilla L., Penicaud L. A role for preadipocytes as macrophage-like cells. FASEB J. 1999; 13, 305–312.

22. Wellen K. E., Hotamisligil G. S. Inflammation, stress, and diabetes. J Clin Invest. 2005; 115, 1111–1119.

23. Michalik L., Auwerx J., Berger J. P., Chatterjee V. K., Glass C. K., Gonzalez F. J., Grimaldi P. A., Kadowaki T., Lazar M. A., O’Rahilly S., Palmer C. N., Plutzky J., Reddy J. K., Spiegelman B. M., Staels B., Wahli W. International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev. 2006; 58(4), 726–741.

24. Belfiore A., Genua M., Malaguarnera R. PPAR-gamma agonists and their effects on IGF-I receptor signaling: implications for cancer. PPAR Res. 2009; 2009: 830501.

25. Berger J., Moller D. E. The mechanisms of action of PPARs. Annu. Rev. Med. 2002; 53, 409–435.

26. Feige J. N., Gelman L., Michalik L., Desvergne B., Wahli W. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res. 2006; 45(2), 120–159. 

27. Moreno S., Farioli-Vecchioli S., Cerù M. P. Immuno localization of peroxisome proliferator-activated receptors and retinoid X receptors in the adult rat CNS. Neuroscience 2004; 123, 131–145. 

28. Heneka M. T., Landreth G. E. PPARs in the brain. Biochim Biophys Acta 2007; 1771, 1031–1045.

29. Lefebvre P., Chinetti G., Fruchart J. C., Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest. 2006; 116, 571–580.

30. Rigamonti E., Chinetti-Gbaguidi G., Staels B. Regulation of macrophage functions by PPAR-alpha, PPAR-gamma, and LXRs in mice and men. Arterioscler Thromb Vasc Biol. 2008; 28, 1050–1059. 

31. Barish G. D., Narkar V. A., Evans R. M. PPAR delta: A dagger in the heart of the metabolic syndrome. J Clin Invest. 2006; 116, 590–597. 

32. Graham T. L., Mookherjee C., Suckling K. E., Palmer C. N., Patel L. The PPAR delta agonist GW0742X reduces atherosclerosis in LDLR (–/–) mice. Atheroscerosis 2005; 181, 29–37. 

33. Ferre P. The biology of peroxisome proliferator-activated receptor. Diabetes 2004; 53, S43–50. 

34. Lehman J. M., Moore L. B., Smith-Oliver T. A., Wilkison W. O., Willson T. M., Kliewer S. A. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor (PPAR gamma) J Biol Chem. 1995; 270, 12953–12956. 

35. Zhang H. Collecting duct-specific deletion of peroxisome proliferator-activated receptor gamma blocks thiazolidinedione-induced fluid retention Proc. Natl. Acad. Sci. USA 2005; 102, 9406–9411.

36. Han S., Roman J. Peroxisome proliferator-activated receptor gamma: a novel target for cancer therapeutics? Anticancer Drugs 2007; 18, 439–445.

37. Betteridge D. J. Thiazolidinediones and fracture risk in patients with type 2 diabetes Diabet. Med. 2011; 28, 759–771.

38. Evans R. M., Barish G. D., Wang Y. X. PPARs and the complex journey to obesity. Nat Med. 2004; 10, 355–361. 

39. Shiraki T., Kamiya N., Shiki S., Kodoma T.S., Kakizuka A., Jingami H. αα,ββ-unsaturated ketone is a core moiety of natural ligands for covalent binding to peroxisome proliferator-activated receptor γγ. J Biol Chem. 2005; 280, 14145–14153.

40. Harte A. L., Mcternan P. G., Mcternan C. L., Smith S. A., Barnett A. H., Kumar S. Rosiglitazone inhibits the insulin-mediated increase in PAI-1 secretion in human abdominal subcutaneous adipocytes. Diabetes Obes Metab. 2003; 5, 302–310.

41. Di Gregorio G. B., Yao-Borengasser A., Rasouli N., Varma V., Lu T., Miles L. M., Ranganathan G., Peterson C. A., Mcgehee R. E., Kern P. A. Expression of CD68 and macrophage chemoattractant protein-1 genes in human adipose and muscle tissues: association with cytokine expression, insulin resistance, and reduction by pioglitazone. Diabetes 2005; 54, 2305–2313.

42. Hammarstedt A., Andersson C. X., Rotter Sopasakis V., Smith U. The effect of PPARγ ligands on the adipose tissue in insulin resistance. Prostaglandins Leukot Essent Fatty Acids. 2005; 73, 65–75.

43. Harte A., Mcternan P., Chetty R., Coppack S., Katz J., Smith S., Kumar S. Insulin-mediated upregulation of the renin angiotensin system in human subcutaneous adipocytes is reduced by rosiglitazone. Circulation 2005; 111, 1954–1961.

44. Forman B. M., Chen J., Evans R. M. Hypolipidemic drugs, polyunsaturated fattyacids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci. 1997; 94(9), 4312–4317.

45. Forman B. M., Tontonoz P., Chen J., Brun R. P., Spiegelman B. M., Evans R. M. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 1995; 83, 803–812.

46. Kliewer S. A., Sundseth S. S., Jones S. A., Brown P. J., Wisely G. B., Koble C. S., Deychand P., Wahli W., Willson T. M., Lenhard J. M., Lehmann J. M. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci. 1997; 94, 4318–4323.

47. Krey G., Braissant O., L’Horset F., Kalkhoven E., Perround M., Parker M. G., Wahli W. Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol. 11, 1997; 779–791.

48. Nagy L., Tontonoz P., Alvarez J. G., Chen H., Evans R. M. Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR-gamma. Cell 1998; 93, 229–240.

49. Berger J., Leibowitz M. D., Doebber T. W., Elbrecht A., Zhang B., Zhou G., Biswas C., Cullinan C. A., Hayes N. S., Li Y., Tanen M., Ventre J., Wu M. S., Berger G. D., Mosley R., Marquis R., Santini C., Sahoo S. P., Tolman R. L., Smith R. G., Moller D. E. Novel peroxisome proliferator-activated receptor PPAR gamma and PPAR delta ligands produce distinct biological effects. J Biol Chem. 1999; 274, 6718–6725.

50. Morino K., Petersen K. F., Shulman G. I. Molecular mechanisms of insulin resistance in humans and their potential links with mitochondrial dysfunction. Diabetes 2006; 55(Suppl 2), 9–15.

51. Pickup J. C., Crook M. A. Is type II diabetes mellitus a disease of the innate immune system? Diabetologia 1998; 41, 1241–1248.

52. Hotamisligil G. S. Inflammation and metabolic disorders. Nature 2006; 444, 860–867.

53. Hevener A. L., Olefsky J. M., Reichart D., Nguyen M. T. A., Bandyopadyhay G., Leung H. Y., Watt M. J., Benner C., Febbraio M. A., Nguyen A. K., Folian B., Subramaniam S., Gonzalez F. J., Glass C. K., Ricote M. Macrophage PPARγ γ is required for normal skeltel muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest. 2007; 117, 1658–1669.

54. Hotamisligil G. S., Arner P., Caro J. F., Atkinson R. L., Spiegelman M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995; 95(5), 2409–2415.

55. Weisberg S. P., Mccann D., Desai M., Rosenbaum M., Leibel R. L., Ferrante Jr. A. W. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112, 1796–1808.

56. Hotamisligil G. S., Shargill N. S., Spiegelman B. M. Adipose expression of tumor necrosis factor-αα: direct role in obesity-linked insulin resistance. Science 1993; 259(5091), 87–91.

57. Toušková V., Haluzík M., Insulin resistance and nitric oxide: molecular mechanisms and pathophysiological associations. Československá fyziologie 2011; 60, 2.

58. Yu Y. H., Ginsberg H. N. Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue. Circulation Research 2005; 96(10), 1042–1052.

59. Weisberg S. P., Hunter D., Huber R., Lemieux J., Slaymaker S., Vaddi K., Charo I., Leibel, R. L., Ferrante Jr. A. W. CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest. 2006; 116, 115–124.

60. Bruun J. M., Lihn A. S., Pedersen S. B., Richelsen B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J Clin Endocrinol Metab. 2005; 90, 2282–2289.

61. Kamei N., Tobe K., Suzuki R., Ohsugi M., Watanabe T., Kubota N., Ohtsuka- Kowatari N., Kumagai K., Sakamoto K., Kobayashi M., Yamauchi T., Ueki K., Oishi Y., Nishimura S., Manabe I., Hashimoto H., Ohnishi Y., Ogata H., Tokuyama K., Tsunoda M., Ide T., Murakami K., Nagai R., Kadowaki T. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J Biol Chem 8. 2006; 281, 26602–26614.

62. Sørensen T. L., Ransohoff R. M., Strieter R. M., Sellebjerg F. Chemokine CCL2 and chemokine receptor CCR2 in early active multiple sclerosis. Eur J Neurol. 2004; 11(7), 445–449.

63. Hayashida K., Nanki T., Girschick H., Yavuz S., Ochi T., Lipsky P. E., Synovial stromal cells from rheumatoid arthritis patients attract monocytes by producing MCP-1 and IL-8. Arthritis Res. 2001; 3(2), 118–126.

64. Kusano K. F., Nakamura K., Kusano H., Nishii N., Banba K., Ikeda T., Hashimoto K., Yamamoto M., Fujio H., Miura A., Ohta K., Morita H., Saito H., Emori T., Nakamura Y., Kusano I., Ohe T. Significance of the level of monocyte chemoattractant protein-1 in human atherosclerosis. Circ J. 2004; 68(7), 671–676.

65. Sartipy P., Loskutoff D. J. Monocyte chemoattractant protein 1 in obesity and insulin resistance. Proc Natl Acad Sci USA 2003; 100(12), 7265–7270.

66. Hotamisligil G. S., Arner P., Caro J. F., Atkinson R. L., Spiegelman B. M. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest. 1995; 95, 2409–2415.

67. Kern P. A., Ranganathan S., Li C., Wood L., Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001; 280, E745–E751.

68. Hotamisligil G. S. Inflammatory pathways and insulin action. International Journal of Obesity and Related Metabolic Disorders 2003; 27(Suppl 3), 53–55.

69. Rotter V., Nagaev I., Smith U. Interleukin-6 (IL-6) induces insulin resistance in 3T3–L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J Biol Chem. 2003; 278, 45777–45784.

70. Aguirre V., Werner E. D., Giraud J., Lee Y. H., Shoelson S. E., White M. F. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem. 2002; 277, 1531–1537.

71. Aguirre V., Werner E. D., Giraud J., Lee Y. H., Shoelson S. E., White M. F. Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. Journal of Biological Chemistry 2002; 277(2), 1531–1537.

72. Nguyen M. T. A., Satoh H., Favelyukis S. JNK and tumor necrosis factor-α mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. Journal of Biological Chemistry 2005; 280(42), 35361–35371.

73. Gao Z., Hwang D., Bataille F. Serine phosphorylation of insulin receptor substrate 1 by inhibitor κB kinase complex. Journal of Biological Chemistry 2002; 277(504), 48115–48121.

74. Yamauchi T., Kamon J., Waki H., Terauchi Y., Kubota N., Hara K., Mori Y., Ide T., Murakimi K., Tsuboyma-Kasaoka N., Ezaki O., Akanuma Y., Gavrilova O., Vinson C., Reitman M. L., Kagechika H., Shudo K., Yoda M., Nakano Y., Tobe K., Nagai R., Kimura S., Tomita M., Froguel P., Kadowaki T. The fatderived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001; 7, 941–946.

75. Chandran M., Phillips S. A., Ciaraldi T., Henry R. R.  Adiponectin: more than just another fat cell hormone. Diabetes Care 2003; 26, 2442–2450.

76. Dietze-Schroeder D., Sell H., Uhlig M., Koenen M., Eckel J. Autocrine action of adiponectin on human fat cells prevents the release of insulin resistance-inducing factors. Diabetes 2005; 54, 2003–2011.

77. Iwaki M., Matsuda M., Maeda N., Funahashi T., Matsuzawa Y., Makishima M., Shimomura I. Induction of adiponectin, a fat-derived antidiabetic and antiatherogenic factor, by nuclear receptors. Diabetes 2003; 52,1655–1663.

78. Choi J. H., Banks A. S., Estall J. L., Kajimura S., Bostrom P., Laznik D., Ruas J. L., Chalmers M. J., Kamenecka T. M., Bluher M., Griffin P. R., Spiegelman B. M. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature 2010; 466, 451–456.

79.  M., Liu F. Up- and down-regulation of adiponectin expression and ultimerization: Mechanisms and therapeutic implication. Biochimie 2012; 94: 2126–2130.

80. Bajaj M., Suraamornkul S., Piper P., Hardies L. J., Glass L., Cersosimo E., Pratipanawatr T., Miyazaki Y., Defronzo R. A. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab. 2004; 89, 200–206.

81. Bouskila M., Pajvani U. B., Scherer P. E. Adiponectin: a relevant player in PPARγγ-agonist-mediated improvements in hepatic insulin sensitivity? Int J Obes Relat Metab Disord. 2005; 29(Suppl 1), S17–S23.

82. Xu H., Barnes G. T., Yang Q., Tan G., Yang D., Cchou C. J., Sole J., Nichols A., Ross J. S., Tartaglia L. A., Chen H. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest. 2003; 112: 1821–1830.

83. Kadowaki T. Yamauchi T. Adiponectin and adiponectin receptors. Endocrine Reviews 2005; 26(3), 439–451.

84. Sharma A. M. Adipose tissue: a mediator of cardiovascular risk. Int J Obes Relat Metab Disord 2002; 26(Suppl 4), S5–S7.

85. Toni R., Malaguti A., Castorina S., Roti E., Lechan R. M. New paradigms in neuroendocrinology: relationships between obesity, systemic inflammation and the neuroendocrine system. J Endocrinol Invest. 2004; 27, 182–186.

86. Heielbronn L., Smith S. R., Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord. 2004; 28(Suppl 4), 12–21.

87. Permana P. A., Menge C., Reaven P. D. Macrophage-secreted factors induce adipocyte inflammation and insulin resistance. Biochem Biophys Res Commun. 2006; 341, 507–514.

88. Arkan M. C., Hevener A. L., Greten F. R. IKK-ββ links inflammation to obesity-induced insulin resistance. Nature Medicine 2005; 11(2), 191–198.

89. Cai D., Yuan M., Frantz D. F. Local and systemic insulin resistance resulting from hepatic activation of IKK-ββ and NF-κκB. Nature Medicine 2005; 11(2), 183–190.

90. Emanuelli B., Glondu M., Filloux C., Peraldi P., Van Obberghen E. The potential role of SOCS-3 in the interleukin-1ββ-induced desensitization of insulin signaling in pancreatic ββ-cells. Diabetes 2004; 53(Suppl 3), S97–S103.

91. Rui L., Aguirre V., Kim J. K., Shulman G. I., Lee A., Corbould A., Dunaif A., White M.F. Insulin/IGF-1 and TNF-αα stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest. 2001; 107, 181–189.

92. Weisberg S. P., Mccann D., Desai M., Rosenbaum M., Leibel R. L., Ferrante A. W. Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003; 112: 1796–1808.

93. Li A. C., Palinovski W. Peroxisome proliferator-activated receptors: how their effects on macrophages can lead to the development of a new drug therapy against atherosclerosis. Annu Rev Pharmacol Toxicol. 2006; 46, 1–39.

94. Chinetti G., Zawadski C., Fruchart J. C., Staels B. Expression of adiponectin receptors in human macrophages and regulation by agonists of the nuclear receptors PPARαα, PPARγγ, and LXR. Biochem Biophys Res Commun. 2004; 314, 151–158.

95. Tsuchida A., Yamauchi T., Takekawa S., Hada Y., Ito Y., Maki T., Kadowski T. Peroxisome proliferator-activated receptor (PPAR)αα activation increases adiponectin receptors and reduces obesity-related Inflammation in adipose tissue: comparison of activation of PPARαα, PPARγγ and their combination. Diabetes 2005; 54, 3358–3370.

96. Kintscher U., Law R. E. PPARγγ-mediated insulin sensitization: the importance of fat versus muscle. Am J Physiol Endocrinol Metab. 2005; 288, E287–E291.

97. Moller D. E., Berger, J. P. Role of PPARs in the regulation of obesity-relatedinsulin sensitivity and inflammation. Int J Obes Relat Metab Disord. 2003; 27(Suppl3), S17–S21.

98. Evans R. M., Barish G. D., Wang Y. X. PPARs and the complex journey to obesity. Med. 2004; 10, 355–361.

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