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Inflammatory lipid mediators in adipocyte function and obesity

Nature Reviews Endocrinology volume 6, pages 71–82 (2010)Cite this article

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Abstract

Survival of multicellular organisms depends on their ability to fight infection, metabolize nutrients, and store energy for times of need. Unsurprisingly, therefore, immunoregulatory and metabolic mechanisms interact in human conditions such as obesity. Both infiltrating immunoinflammatory cells and adipocytes play critical roles in the modulation of metabolic homeostasis, so it is important to understand factors that regulate both adipocyte and immune cell function. A currently favored paradigm for obesity-associated metabolic dysfunction is that chronic macronutrient and/or lipid overload (associated with adiposity) induces cellular stress that initiates and perpetuates an inflammatory cycle and pathophysiological signaling of immunoinflammatory cells and adipocytes. Many lipid mediators exert their biological effects by binding to cognate receptors, such as G-protein-coupled receptors and Toll-like receptors. This process is tightly regulated under normal physiological conditions, and any disruption can initiate disease processes. Observations that cellular lipid loading (associated with adiposity) initiates inflammatory events has encouraged studies on the role of lipid mediators. In this review, we speculate that lipid mediators act on important immune receptors to induce low-grade tissue inflammation, which leads to adipocyte and metabolic dysfunction.

Key Points

  • The idea that chronic low-grade inflammation underlies obesity and metabolic dysfunction has become credible in recent years

  • Clinical studies have shown that excess macronutrient intake promotes signs of inflammatory stress and leads to metabolic dysfunction

  • Metabolic dysfunction may not be just a disease of obesity but a disease of dysfunctional adipocytes, induced either by excess feeding (obesity), malnutrition, starvation or possibly an immunoinflammatory disorder

  • Elevation of the concentration of circulating and adipose-tissue-localized inflammatory lipid mediators contributes to inflammatory cell activation, adipocyte growth, development and dysfunction, which leads to metabolic disturbances

  • Lipid mediators might induce adipocyte dysfunction in obesity by over-stimulating or inhibiting cognate receptors, such as G-protein-coupled receptors and Toll-like receptors

  • Immune system modulation might provide a means to intervene and re-establish tolerance to the abnormal metabolic homeostasis that occurs in obesity

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Figure 1: Obesity, metabolic syndrome and inflammation citations as a function of year from 1995.
Figure 2: Inflammatory cells and adipocytes in adipose tissue in obesity.
Figure 3: Important lipid mediators in obesity and metabolic dysfunction.

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References

  1. Powell, K. Obesity: the two faces of fat. Nature 447, 525–527 (2007).

    Article  CAS  PubMed  Google Scholar 

  2. Van Gaal, L. F., Mertens, I. L. & De Block, C. E. Mechanisms linking obesity with cardiovascular disease. Nature 444, 875–880 (2006).

    Article  CAS  PubMed  Google Scholar 

  3. Eckel, R. H., Grundy, S. M. & Zimmet, P. Z. The metabolic syndrome. Lancet 365, 1415–1428 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Alberti, K. G., Zimmet, P. & Shaw, J. The metabolic syndrome—a new worldwide definition. Lancet 366, 1059–1062 (2005).

    Article  PubMed  Google Scholar 

  5. Dandona, P., Aljada, A., Chaudhuri, A., Mohanty, P. & Garg, R. Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation. Circulation 111, 1448–1454 (2005).

    Article  PubMed  Google Scholar 

  6. Mohanty, P. et al. Glucose challenge stimulates reactive oxygen species (ROS) generation by leucocytes. J. Clin. Endocrinol. Metab. 85, 2970–2973 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Aljada, A. et al. Glucose intake induces an increase in activator protein 1 and early growth response 1 binding activities, in the expression of tissue factor and matrix metalloproteinase in mononuclear cells, and in plasma tissue factor and matrix metalloproteinase concentrations. Am. J. Clin. Nutr. 80, 51–57 (2004).

    Article  CAS  PubMed  Google Scholar 

  8. Das, U. N. Is obesity an inflammatory condition? Nutrition 17, 953–966 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Unger, R. H. Lipid overload and overflow: metabolic trauma and the metabolic syndrome. Trends Endocrinol. Metab. 14, 398–403 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Pickup, J. C. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 27, 813–823 (2004).

    Article  PubMed  Google Scholar 

  11. Duncan, B. B. et al. Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes 52, 1799–1805 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Odegaard, J. I. et al. Macrophage-specific PPARγ controls alternative activation and improves insulin resistance. Nature 447, 1116–1120 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Plutzky, J. Expansion and contraction: the mighty, mighty fatty acid. Nat. Med. 15, 618–619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bastard, J. P. et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur. Cytokine Netw. 17, 4–12 (2006).

    CAS  PubMed  Google Scholar 

  16. Caballero, A. E. Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obes. Res. 11, 1278–1289 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Visser, M., Bouter, L. M., McQuillan, G. M., Wener, M. H. & Harris, T. B. Elevated C-reactive protein levels in overweight and obese adults. JAMA 282, 2131–2135 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Esposito, K. et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. JAMA 289, 1799–1804 (2003).

    Article  CAS  PubMed  Google Scholar 

  19. Ridker, P. M., Buring, J. E., Cook, N. R. & Rifai, N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation 107, 391–397 (2003).

    Article  PubMed  Google Scholar 

  20. Dandona, P. et al. Inhibitory effect of a two day fast on reactive oxygen species (ROS) generation by leucocytes and plasma ortho-tyrosine and meta-tyrosine concentrations. J. Clin. Endocrinol. Metab. 86, 2899–2902 (2001).

    Article  CAS  PubMed  Google Scholar 

  21. Serpillon, S. et al. Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. Am. J. Physiol. Heart Circ. Physiol. 297, H153–H162 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nijhuis, J. et al. Neutrophil activation in morbid obesity, chronic activation of acute inflammation. Obesity 17, 2014–2018 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Dandona. P., Chaudhuri, A., Ghanim, H. & Mohanty, P. Insulin as an anti-inflammatory and antiatherogenic modulator. J. Am. Coll. Cardiol. 53 (Suppl. 1), S14–S20 (2009).

    Article  CAS  PubMed  Google Scholar 

  24. Dhindsa, S. et al. Differential effects of glucose and alcohol on reactive oxygen species generation and intranuclear nuclear factor-kappaB in mononuclear cells. Metabolism 53, 330–334 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293, 1673–1677 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Renna, N. F., Vazquez, M. A., Lama, M. C., Gonzalez, E. S. & Miatello, R. M. Effect of chronic aspirin administration on an experimental model of metabolic syndrome. Clin. Exp. Pharmacol. Physiol. 36, 162–168 (2009).

    Article  CAS  PubMed  Google Scholar 

  27. Van Kerckhoven, R., Kalkman, E. A., Saxena, P. R. & Schoemaker, R. G. Altered cardiac collagen and associated changes in diastolic function of infarcted rat hearts. Cardiovasc. Res. 46, 316–323 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Larsen, C. M. et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517–1526 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Larsen, C. M. et al. Sustained effects of interleukin-1 receptor antagonist treatment in type 2 diabetes. Diabetes Care 32, 1663–1668 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Wilson, P. W. Evidence of systemic inflammation and estimation of coronary artery disease risk: a population perspective. Am. J. Med. 121 (Suppl. 1), S15–S20 (2008).

    Article  PubMed  Google Scholar 

  31. Libby, P. Role of inflammation in atherosclerosis associated with rheumatoid arthritis. Am. J. Med. 121 (Suppl. 1), S21–S31 (2008).

    Article  CAS  PubMed  Google Scholar 

  32. Dandona, P. et al. Angiotensin II receptor blocker valsartan suppresses reactive oxygen species generation in leukocytes, nuclear factor-kappa B, in mononuclear cells of normal subjects: evidence of an antiinflammatory action. J. Clin. Endocrinol. Metab. 88, 4496–4501 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Koh, K. K., Han, S. H. & Quon, M. J. Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions. J. Am. Coll. Cardiol. 46, 1978–1985 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Paraskevas, K. I., Stathopoulos, V. & Mikhailidis, D. P. Pleiotropic effects of statins: implications for a wide range of diseases. Curr. Vasc. Pharmacol. 6, 237–239 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Jankowski, P., Safar, M. E. & Benetos, A. Pleiotropic effects of drugs inhibiting the renin–angiotensin–aldosterone system. Curr. Pharm. Des. 15, 571–584 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Aljada, A. et al. Troglitazone reduces the expression of PPARγ while stimulating that of PPARα in mononuclear cells in obese subjects. J. Clin. Endocrinol. Metab. 86, 3130–3133 (2001).

    CAS  PubMed  Google Scholar 

  37. Mohanty, P. et al. Evidence for a potent antiinflammatory effect of rosiglitazone. J. Clin. Endocrinol. Metab. 89, 2728–2735 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Singh, R. et al. Autophagy regulates lipid metabolism. Nature 458, 1131–1135 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Jaworski, K. et al. AdPLA ablation increases lipolysis and prevents obesity induced by high-fat feeding or leptin deficiency. Nat. Med. 15, 159–168 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Duncan, R. E., Ahmadian, M., Jaworski, K., Sarkadi-Nagy, E. & Sul, H. S. Regulation of lipolysis in adipocytes. Annu. Rev. Nutr. 27, 79–101 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Park, K. W., Halperin, D. S. & Tontonoz, P. Before they were fat: adipocyte progenitors. Cell. Metab. 8, 454–457 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Pages, C., Simon, M. F., Valet, P. & Saulnier-Blache, J. S. Lysophosphatidic acid synthesis and release. Prostaglandins Other Lipid Mediat. 64, 1–10 (2001).

    Article  CAS  PubMed  Google Scholar 

  43. Ailhaud, G., Guesnet, P. & Cunnane, S. C. An emerging risk factor for obesity: does disequilibrium of polyunsaturated fatty acid metabolism contribute to excessive adipose tissue development? Br. J. Nutr. 100, 461–470 (2008).

    Article  CAS  PubMed  Google Scholar 

  44. Weisberg, S. P. et al. Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Cinti, S. The adipose organ. Prostaglandins Leukot. Essent. Fatty Acids 73, 9–15 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921–929 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hotamisligil, G. S. Inflammation and metabolic disorders. Nature 444, 860–867 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Lumeng, C. N., Maillard, I. & Saltiel, A. R. T-ing up inflammation in fat. Nat. Med. 15, 846–847 (2009).

    Article  CAS  PubMed  Google Scholar 

  49. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930–939 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nishimura, S. et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914–920 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002).

    Article  CAS  PubMed  Google Scholar 

  52. Medzhitov, R. Origin and physiological roles of inflammation. Nature 454, 428–435 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Charriere, G. et al. Preadipocyte conversion to macrophage. Evidence of plasticity. J. Biol. Chem. 278, 9850–9855 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Clement, K. et al. Weight loss regulates inflammation-related genes in white adipose tissue of obese subjects. FASEB J. 18, 1657–1669 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. van Dielen, F. M., Buurman, W. A., Hadfoune, M., Nijhuis, J. & Greve, J. W. Macrophage inhibitory factor, plasminogen activator inhibitor-1, other acute phase proteins, and inflammatory mediators normalize as a result of weight loss in morbidly obese subjects treated with gastric restrictive surgery. J. Clin. Endocrinol. Metab. 89, 4062–4068 (2004).

    Article  CAS  PubMed  Google Scholar 

  56. Cottam, D. R. et al. The chronic inflammatory hypothesis for the morbidity associated with morbid obesity: implications and effects of weight loss. Obes. Surg. 14, 589–600 (2004).

    Article  PubMed  Google Scholar 

  57. Nawrocki, A. R. & Scherer, P. E. Keynote review: the adipocyte as a drug discovery target. Drug Discov. Today 10, 1219–1230 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Spiegelman, B. M. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes 47, 507–514 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Amri, E. Z., Bertrand, B., Ailhaud, G. & Grimaldi, P. Regulation of adipose cell differentiation. I. Fatty acids are inducers of the AP2 gene expression. J. Lipid Res. 32, 1449–1456 (1991).

    CAS  PubMed  Google Scholar 

  60. Aubert, J., Ailhaud, G. & Negrel, R. Evidence for a novel regulatory pathway activated by (carba)prostacyclin in preadipose and adipose cells. FEBS Lett. 397, 117–121 (1996).

    Article  CAS  PubMed  Google Scholar 

  61. Ailhaud, G., Grimaldi, P. & Negrel, R. Cellular and molecular aspects of adipose tissue development. Annu. Rev. Nutr. 12, 207–233 (1992).

    Article  CAS  PubMed  Google Scholar 

  62. Ailhaud, G. Some new aspects on adipose tissue development. Diabetes Metab. Rev. 8, 3–7 (1992).

    Article  CAS  PubMed  Google Scholar 

  63. Spiegelman, B. M. & Flier, J. S. Adipogenesis and obesity: rounding out the big picture. Cell 87, 377–389 (1996).

    Article  CAS  PubMed  Google Scholar 

  64. Hauner, H. et al. Promoting effect of glucocorticoids on the differentiation of human adipocyte precursor cells cultured in a chemically defined medium. J. Clin. Invest. 84, 1663–1670 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Shimizu, T. Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu. Rev. Pharmacol. Toxicol. 49, 123–150 (2009).

    Article  CAS  PubMed  Google Scholar 

  66. Ghanim, H. et al. Increase in plasma endotoxin concentrations and the expression of Toll like receptors and suppressor of cytokine signaling-3 in mononuclear cells following a high fat high carbohydrate meal: implications for insulin resistance. Diabetes Care 32, 2281–2287 (2009).

  67. Dandona, P., Chaudhuri, A., Ghanim, H. & Mohanty, P. Anti-inflammatory effects of insulin and pro-inflammatory effects of glucose: relevance to the management of acute myocardial infarction and other acute coronary syndromes. Rev. Cardiovasc. Med. 7 (Suppl. 2), S25–S34 (2006).

    PubMed  Google Scholar 

  68. Dandona, P. The link between insulin resistance syndrome and inflammatory markers. Endocr. Pract. 9 (Suppl. 2), 53–57 (2003).

    Article  PubMed  Google Scholar 

  69. Dandona, P., Aljada, A., Chaudhuri, A. & Bandyopadhyay, A. The potential influence of inflammation and insulin resistance on the pathogenesis and treatment of atherosclerosis-related complications in type 2 diabetes. J. Clin. Endocrinol. Metab. 88, 2422–2429 (2003).

    Article  CAS  PubMed  Google Scholar 

  70. Williams, E. S., Baylin, A. & Campos, H. Adipose tissue arachidonic acid and the metabolic syndrome in Costa Rican adults. Clin. Nutr. 26, 474–482 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Garaulet, M. et al. Site-specific differences in the fatty acid composition of abdominal adipose tissue in an obese population from a Mediterranean area: relation with dietary fatty acids, plasma lipid profile, serum insulin, and central obesity. Am. J. Clin. Nutr. 74, 585–591 (2001).

    Article  CAS  PubMed  Google Scholar 

  72. Decsi, T., Molnar, D. & Koletzko, B. Long-chain polyunsaturated fatty acids in plasma lipids of obese children. Lipids 31, 305–311 (1996).

    Article  CAS  PubMed  Google Scholar 

  73. Savva, S. C. et al. Association of adipose tissue arachidonic acid content with BMI and overweight status in children from Cyprus and Crete. Br. J. Nutr. 91, 643–649 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Weiler, H. A. Dietary supplementation of arachidonic acid is associated with higher whole body weight and bone mineral density in growing pigs. Pediatr. Res. 47, 692–697 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Jensen, C. L. et al. Effect of dietary linoleic/alpha-linolenic acid ratio on growth and visual function of term infants. J. Pediatr. 131, 200–209 (1997).

    Article  CAS  PubMed  Google Scholar 

  76. Duncan, R. E., Sarkadi-Nagy, E., Jaworski, K., Ahmadian, M. & Sul, H. S. Identification and functional characterization of adipose-specific phospholipase A2 (AdPLA). J. Biol. Chem. 283, 25428–25436 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Ii, H., Hatakeyama, S., Tsutsumi, K., Sato, T. & Akiba, S. Group IVA phospholipase A2 is associated with the storage of lipids in adipose tissue and liver. Prostaglandins Other Lipid Mediat. 86, 12–17 (2008).

    Article  CAS  PubMed  Google Scholar 

  78. Satake, Y. et al. Role of group V phospholipase A2 in zymosan-induced eicosanoid generation and vascular permeability revealed by targeted gene disruption. J. Biol. Chem. 279, 16488–16494 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Balsinde, J., Winstead, M. V. & Dennis, E. A. Phospholipase A2 regulation of arachidonic acid mobilization. FEBS Lett. 531, 2–6 (2002).

    Article  CAS  PubMed  Google Scholar 

  80. Levick, S. et al. Antifibrotic activity of an inhibitor of group IIA secretory phospholipase A2 in young spontaneously hypertensive rats. J. Immunol. 176, 7000–7007 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Degousee, N. et al. Groups, IV, V, and X phospholipases A2 s in human neutrophils: role in eicosanoid production and gram-negative bacterial phospholipid hydrolysis. J. Biol. Chem. 277, 5061–5073 (2002).

    Article  CAS  PubMed  Google Scholar 

  82. Harizi, H., Corcuff, J. B. & Gualde, N. Arachidonic-acid-derived eicosanoids: roles in biology and immunopathology. Trends Mol. Med. 14, 461–469 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Narumiya, S. & FitzGerald, G. A. Genetic and pharmacological analysis of prostanoid receptor function. J. Clin. Invest. 108, 25–30 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gupta, R. A. et al. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc. Natl Acad. Sci. USA 97, 13275–13280 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Forman, B. M. et al. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 83, 803–812 (1995).

    Article  CAS  PubMed  Google Scholar 

  86. Pierce, K. L. & Regan, J. W. Prostanoid receptor heterogeneity through alternative mRNA splicing. Life Sci. 62, 1479–1483 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Sugimoto, Y. & Narumiya, S. Prostaglandin E receptors. J. Biol. Chem. 282, 11613–11617 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Vane, J. R., Bakhle, Y. S. & Botting, R. M. Cyclooxygenases 1 and 2. Annu. Rev. Pharmacol. Toxicol. 38, 97–120 (1998).

    Article  CAS  PubMed  Google Scholar 

  89. Bos, C. L., Richel, D. J., Ritsema, T., Peppelenbosch, M. P. & Versteeg, H. H. Prostanoids and prostanoid receptors in signal transduction. Int. J. Biochem. Cell Biol. 36, 1187–1205 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Kim, S. & Moustaid-Moussa, N. Secretory, endocrine and autocrine/paracrine function of the adipocyte. J. Nutr. 130 (Suppl.), S3110–S3115 (2000).

    Article  Google Scholar 

  91. Shillabeer, G., Kumar, V., Tibbo, E. & Lau, D. C. Arachidonic acid metabolites of the lipoxygenase as well as the cyclooxygenase pathway may be involved in regulating preadipocyte differentiation. Metabolism 47, 461–466 (1998).

    Article  CAS  PubMed  Google Scholar 

  92. Fain, J. N., Leffler, C. W. & Bahouth, S. W. Eicosanoids as endogenous regulators of leptin release and lipolysis by mouse adipose tissue in primary culture. J. Lipid Res. 41, 1689–1694 (2000).

    CAS  PubMed  Google Scholar 

  93. Fain, J. N. & Bahouth, S. W. Regulation of leptin release by mammalian adipose tissue. Biochem. Biophys. Res. Commun. 274, 571–575 (2000).

    Article  CAS  PubMed  Google Scholar 

  94. Enomoto, N. et al. Kupffer cell-derived prostaglandin E2 is involved in alcohol-induced fat accumulation in rat liver. Am. J. Physiol. Gastrointest. Liver Physiol. 279, G100–G106 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Perez, S., Aspichueta, P., Ochoa, B. & Chico, Y. The 2-series prostaglandins suppress VLDL secretion in an inflammatory condition-dependent manner in primary rat hepatocytes. Biochim. Biophys. Acta 1761, 160–171 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Massiera, F. et al. Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern? J. Lipid Res. 44, 271–279 (2003).

    Article  CAS  PubMed  Google Scholar 

  97. Mazid, M. A. et al. Endogenous 15-deoxy-Δ12-prostaglandin J2 synthesized by adipocytes during maturation phase contributes to upregulation of fat storage. FEBS Lett. 580, 6885–6890 (2006).

    Article  CAS  PubMed  Google Scholar 

  98. Vassaux, G., Negrel, R., Ailhaud, G. & Gaillard, D. Proliferation and differentiation of rat adipose precursor cells in chemically defined medium: differential action of anti-adipogenic agents. J. Cell Physiol. 161, 249–256 (1994).

    Article  CAS  PubMed  Google Scholar 

  99. Liu, L. & Clipstone, N. A. Prostaglandin F2α inhibits adipocyte differentiation via a Gαq-calcium-calcineurin-dependent signaling pathway. J. Cell Biochem. 100, 161–173 (2007).

    Article  CAS  PubMed  Google Scholar 

  100. Goodwill, A. G., James, M. E. & Frisbee, J. C. Increased vascular thromboxane generation impairs dilation of skeletal muscle arterioles of obese Zucker rats with reduced oxygen tension. Am. J. Physiol. Heart Circ. Physiol. 295, H1522–H1528 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Homaidan, F. R., Chakroun, I., Haidar, H. A. & El-Sabban, M. E. Protein regulators of eicosanoid synthesis: role in inflammation. Curr. Protein Pept. Sci. 3, 467–484 (2002).

    Article  CAS  PubMed  Google Scholar 

  102. Brink, C. Leukotriene receptors: state of the art. Adv. Exp. Med. Biol. 525, 7–10 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Camara, N. O., Martins, J. O., Landgraf, R. G. & Jancar, S. Emerging roles for eicosanoids in renal diseases. Curr. Opin. Nephrol. Hypertens. 18, 21–27 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Back, M., Sultan, A., Ovchinnikova, O. & Hansson, G. K. 5-Lipoxygenase-activating protein: a potential link between innate and adaptive immunity in atherosclerosis and adipose tissue inflammation. Circ. Res. 100, 946–949 (2007).

    Article  PubMed  CAS  Google Scholar 

  105. Madsen, L. et al. Adipocyte differentiation of 3T3-L1 preadipocytes is dependent on lipoxygenase activity during the initial stages of the differentiation process. Biochem. J. 375, 539–549 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Nunemaker, C. S. et al. 12-Lipoxygenase-knockout mice are resistant to inflammatory effects of obesity induced by Western diet. Am. J. Physiol. Endocrinol. Metab. 295, E1065–E1075 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Maya-Monteiro, C. M. et al. Leptin induces macrophage lipid body formation by a phosphatidylinositol 3-kinase- and mammalian target of rapamycin-dependent mechanism. J. Biol. Chem. 283, 2203–2210 (2008).

    Article  CAS  PubMed  Google Scholar 

  108. József, L., Zouki, C., Petasis, N. A., Serhan, C. N. & Filep, J. G. Lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 inhibit peroxynitrite formation, NF-kappa B and AP-1 activation, and IL-8 gene expression in human leukocytes. Proc. Natl Acad. Sci. USA 99, 13266–13271 (2002).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  109. Perretti, M. et al. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor. Nat. Med. 8, 1296–1302 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Serhan, C. N. et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025–1037 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Serhan, C. N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 6, 1191–1197 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Serhan, C. N., Chiang, N. & Van Dyke, T. E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol. 8, 349–361 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Inceoglu, B., Schmelzer, K. R., Morisseau, C., Jinks, S. L. & Hammock, B. D. Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs). Prostaglandins Other Lipid Mediat. 82, 42–49 (2007).

    Article  CAS  PubMed  Google Scholar 

  114. Spector, A. A. & Norris, A. W. Action of epoxyeidosatrienoic acids on cellular function. Am. J. Physiol. Cell. Physiol. 292, C996–C1012 (2007).

    Article  CAS  PubMed  Google Scholar 

  115. De Taeye, B. M. et al. Expression and regulation of soluble epoxide hydrolase in adipose tissue. Obesity doi:10.1038/oby.2009.227.

  116. Ai, D. et al. Angiotensin II up-regulates soluble epoxide hydrolase in vascular endothelium in vitro and in vivo. Proc. Natl Acad. Sci. USA 104, 9018–9023 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hammock, B. D. & Ota, K. Differential induction of cytosolic epoxide hydrolase, microsomal epoxide hydrolase, and glutathione S-transferase activities. Toxicol. App. Pharmacol. 71, 254–265 (1983).

    Article  CAS  Google Scholar 

  118. Campbell, W. B. New role for epoxyeicosatrienoic acids as anti-inflammatory mediators. Trends Pharmacol. Sci. 21, 125–127 (2000).

    Article  CAS  PubMed  Google Scholar 

  119. Node, K. et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285, 1276–1279 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Schmelzer, K. R. et al. Enhancement of antinociception by coadministration of nonsteroidal anti-inflammatory drugs and soluble epoxide hydrolase inhibitors. Proc. Natl Acad. Sci. USA 103, 13646–13651 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Lee, C. R. et al. Genetic variation in soluble epoxide hydrolase (EPHX2) and risk of coronary heart disease: The Atherosclerosis Risk in Communities (ARIC) study. Hum. Mol. Genet. 15, 1640–1649 (2006).

    Article  CAS  PubMed  Google Scholar 

  122. Ohtoshi, K. et al. Association of soluble epoxide hydrolase gene polymorphism with insulin resistance in type 2 diabetic patients. Biochem. Biophys. Res. Commun. 331, 347–350 (2005).

    Article  CAS  PubMed  Google Scholar 

  123. Burdon, K. P. et al. Genetic analysis of the soluble epoxide hydrolase gene, EPHX2, in subclinical cardiovascular disease in the Diabetes Heart Study. Diab. Vasc. Dis. Res. 5, 128–134 (2008).

    Article  PubMed  Google Scholar 

  124. Gountopoulou, A., Leondaritis, G., Galanopoulou, D. & Mavri-Vavayanni, M. TNFα is a potent inducer of platelet-activating factor synthesis in adipocytes but not in preadipocytes. Differential regulation by PI3K. Cytokine 41, 174–181 (2008).

    Article  CAS  PubMed  Google Scholar 

  125. Samad, F., Hester, K. D., Yang, G., Hannun, Y. A. & Bielawski, J. Altered adipose and plasma sphingolipid metabolism in obesity: a potential mechanism for cardiovascular and metabolic risk. Diabetes 55, 2579–2587 (2006).

    Article  CAS  PubMed  Google Scholar 

  126. Di Marzo, V. Targeting the endocannabinoid system: to enhance or reduce? Nat. Rev. Drug Discov. 7, 438–455 (2008).

    Article  CAS  PubMed  Google Scholar 

  127. Kudolo, G. B., Bressler, P. & DeFronzo, R. A. Plasma PAF acetylhydrolase in non-insulin dependent diabetes mellitus and obesity: effect of hyperinsulinemia and lovastatin treatment. J. Lipid Mediat. Cell Signal. 17, 97–113 (1997).

    Article  CAS  PubMed  Google Scholar 

  128. Okada, T. et al. Platelet-activating factor acetylhydrolase concentration in children with abdominal obesity. Arterioscler. Thromb. Vasc. Biol. 26, e40–e41 (2006).

    Article  CAS  PubMed  Google Scholar 

  129. Jones, D. End of the line for cannabinoid receptor 1 as an anti-obesity target? Nat. Rev. Drug Discov. 7, 961–962 (2008).

    Article  CAS  PubMed  Google Scholar 

  130. Cooke, D. & Bloom, S. The obesity pipeline: current strategies in the development of anti-obesity drugs. Nat. Rev. Drug Discov. 5, 919–931 (2006).

    Article  CAS  PubMed  Google Scholar 

  131. Janero, D. R. & Makriyannis, A. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis. Expert Opin. Emerg. Drugs 14, 43–65 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Yudkin, J. S., Kumari, M., Humphries, S. E. & Mohamed-Ali, V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148, 209–214 (2000).

    Article  CAS  PubMed  Google Scholar 

  133. Xu, H. et al. Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Wang, Y. X. et al. Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113, 159–170 (2003).

    Article  CAS  PubMed  Google Scholar 

  135. Rajala, M. W., Obici, S., Scherer, P. E. & Rossetti, L. Adipose-derived resistin and gut-derived resistin-like molecule-beta selectively impair insulin action on glucose production. J. Clin. Invest. 111, 225–230 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Dandona, P., Aljada, A. & Bandyopadhyay, A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol. 25, 4–7 (2004).

    Article  CAS  PubMed  Google Scholar 

  137. Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-kB. Nat. Med. 11, 183–190 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Arkan, M. C. et al. IKK-β links inflammation to obesity-induced insulin resistance. Nat. Med. 11, 191–198 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Masoudi, F. A. et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation 111, 583–590 (2005).

    Article  CAS  PubMed  Google Scholar 

  140. Christiansen, T., Richelsen, B. & Bruun, J. M. Monocyte chemoattractant protein-1 is produced in isolated adipocytes, associated with adiposity and reduced after weight loss in morbid obese subjects. Int. J. Obes. (Lond.) 29, 146–150 (2005).

    Article  CAS  Google Scholar 

  141. Shoelson, S. E., Herrero, L. & Naaz, A. Obesity, inflammation, and insulin resistance. Gastroenterology 132, 2169–2180 (2007).

    Article  CAS  PubMed  Google Scholar 

  142. Kim, F. et al. Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ. Res. 100, 1589–1596 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Heilbronn, L. K. & Campbell, L. V. Adipose tissue macrophages, low grade inflammation and insulin resistance in human obesity. Curr. Pharm. Des. 14, 1225–1230 (2008).

    Article  CAS  PubMed  Google Scholar 

  144. Cani, P. D. et al. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470–1481 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Rocha, V. Z. et al. Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ. Res. 103, 467–476 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. School of Biomedical Sciences, The University of Queensland, Brisbane, 4072, QLD, Australia

    Abishek Iyer

  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, 4072, QLD, Australia

    David P. Fairlie

  3. Diamantina Institute for Cancer, Immunology and Metabolic Medicine, The University of Queensland, Brisbane, 4072, QLD, Australia

    Johannes B. Prins

  4. Department of Entomology and Cancer Center, University of California, Davis, 95616, CA, USA

    Bruce D. Hammock

  5. Faculty of Sciences, University of Southern Queensland, Toowoomba, 4350, QLD, Australia

    Lindsay Brown

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Correspondence to Lindsay Brown.

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Competing interests

J. B. Prins is founder and scientific director of Adipogen Pty Ltd, a spin-out company with initial shareholding by Queensland Government and The University of Queensland. Adipogen has patents in the field of anti-obesity therapeutics.

Bruce D. Hammond is the founder of Arête Therapeutics. This company is moving sEH inhibitors through clinical trials for treatment of hypertension, pain, metabolic disease, inflammation and other disorders. The other authors declare no competing interests.

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Iyer, A., Fairlie, D., Prins, J. et al. Inflammatory lipid mediators in adipocyte function and obesity. Nat Rev Endocrinol 6, 71–82 (2010). https://doi.org/10.1038/nrendo.2009.264

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