Obesity, Inflammation, and Insulin Resistance

  • Lesley G. Ellies
  • Andrew Johnson
  • Jerrold M. OlefskyEmail author
Part of the Energy Balance and Cancer book series (EBAC, volume 7)


Obesity is a pressing public health concern as it leads to a collection of abnormalities often termed the metabolic syndrome. Molecular studies are revealing novel pathways by which obesity-associated hormonal, nutrient, and tissue ­factors can stimulate the chronic low-grade inflammation that leads to insulin resistance. Signaling interactions between proinflammatory immune cells, particularly macrophages and lymphocytes, and insulin target cells in the liver and adipose tissue are key to this process and provide potential opportunities for the development of targeted therapies to improve insulin sensitivity and correct energy imbalance.


Insulin Resistance Treg Cell Unfold Protein Response Visceral Adipose Tissue Neutrophil Elastase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Adipose tissue macrophage


Diet-induced obesity


Free fatty acid


G protein-coupled receptor


High-fat diet




Subcutaneous adipose tissue


Saturated fatty acid


Tumor necrosis factor


Visceral adipose tissue


White adipose tissue



This work was supported by NIH grant U54CA155435 and DOD grant BC102147.


  1. 1.
    Flegal KM, Carroll MD, Ogden CL, Curtin LR (2010) Prevalence and trends in obesity among US adults, 1999–2008. JAMA 303(3):235–241. doi:2009.2014[pii].10.1001/jama.2009.2014PubMedGoogle Scholar
  2. 2.
    Moller DE, Kaufman KD (2005) Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 56:45–62. doi:10.1146/ Scholar
  3. 3.
    James PT, Leach R, Kalamara E, Shayeghi M (2001) The worldwide obesity epidemic. Obes Res 9(suppl 4):228S–233S. doi: 10.1038/oby.2001.123 PubMedGoogle Scholar
  4. 4.
    Johnson AR, Justin Milner J, Makowski L (2012) The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev 249(1):218–238. doi: 10.1111/j.1600-065X.2012.01151.x PubMedGoogle Scholar
  5. 5.
    Ogden CL, Carroll MD, Kit BK, Flegal KM (2012) Prevalence of obesity in the United States, 2009–2010, vol NCHS data brief, no 82. National Center for Health Statistics, Hyattsville, MDGoogle Scholar
  6. 6.
    Li P, Fan W, Xu J, Lu M, Yamamoto H, Auwerx J, Sears DD, Talukdar S, Oh D, Chen A, Bandyopadhyay G, Scadeng M, Ofrecio JM, Nalbandian S, Olefsky JM (2011) Adipocyte NCoR knockout decreases PPARgamma phosphorylation and enhances PPARgamma activity and insulin sensitivity. Cell 147(4):815–826. doi:S0092-8674(11)01220-7[pii].10.1016/j.cell.2011.09.050PubMedGoogle Scholar
  7. 7.
    Jacobi D, Stanya KJ, Lee CH (2012) Adipose tissue signaling by nuclear receptors in metabolic complications of obesity. Adipocyte 1(1):4–12. doi: 10.4161/adip.19036 PubMedGoogle Scholar
  8. 8.
    Hotamisligil GS, Shargill NS, Spiegelman BM (1993) Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259(5091):87–91PubMedGoogle Scholar
  9. 9.
    Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830. doi:10.1172/JCI19451. 112/12/1821[pii]PubMedGoogle Scholar
  10. 10.
    Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12):1796–1808. doi: 10.1172/JCI19246 PubMedGoogle Scholar
  11. 11.
    Galic S, Oakhill JS, Steinberg GR (2010) Adipose tissue as an endocrine organ. Mol Cell Endocrinol 316(2):129–139. doi:S0303-7207(09)00438-9[pii].10.1016/j.mce.2009.08.018PubMedGoogle Scholar
  12. 12.
    Despres JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444(7121):881–887. doi: 10.1038/nature05488 PubMedGoogle Scholar
  13. 13.
    Kissebah AH, Vydelingum N, Murray R, Evans DJ, Hartz AJ, Kalkhoff RK, Adams PW (1982) Relation of body fat distribution to metabolic complications of obesity. J Clin Endocrinol Metab 54(2):254–260PubMedGoogle Scholar
  14. 14.
    Nedungadi TP, Clegg DJ (2009) Sexual dimorphism in body fat distribution and risk for cardiovascular diseases. J Cardiovasc Transl Res 2(3):321–327. doi: 10.1007/s12265-009-9101-1 PubMedGoogle Scholar
  15. 15.
    Ford ES, Li C, Zhao G, Pearson WS, Mokdad AH (2008) Prevalence of the metabolic syndrome among U.S. adolescents using the definition from the International Diabetes Federation. Diabetes Care 31(3):587–589. doi: 10.2337/dc07-1030 PubMedGoogle Scholar
  16. 16.
    Anderson GL, Neuhouser ML (2012) Obesity and the risk for premenopausal and postmenopausal breast cancer. Cancer Prev Res 5(4):515–521. doi: 10.1158/1940-6207.CAPR-12-0091 Google Scholar
  17. 17.
    Vona-Davis L, Rose DP (2012) Type 2 diabetes and obesity metabolic interactions: common factors for breast cancer risk and novel approaches to prevention and therapy. Curr Diabetes Rev 8(2):116–130. doi:EPUB-CDR-20120117-002[pii]PubMedGoogle Scholar
  18. 18.
    Cleary MP, Grossmann ME (2009) Minireview: obesity and breast cancer: the estrogen connection. Endocrinology 150(6):2537–2542. doi:en.2009-0070[pii].10.1210/en.2009-0070PubMedGoogle Scholar
  19. 19.
    Siddle K (2012) Molecular basis of signaling specificity of insulin and IGF receptors: neglected corners and recent advances. Front Endocrinol (Lausanne) 3:34. doi: 10.3389/fendo.2012.00034 Google Scholar
  20. 20.
    Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS (2002) A central role for JNK in obesity and insulin resistance. Nature 420(6913):333–336. doi: 10.1038/nature01137 PubMedGoogle Scholar
  21. 21.
    Yuan M, Konstantopoulos N, Lee J, Hansen L, Li ZW, Karin M, Shoelson SE (2001) Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293(5535):1673–1677. doi: 10.1126/science.1061620 PubMedGoogle Scholar
  22. 22.
    Perseghin G, Petersen K, Shulman GI (2003) Cellular mechanism of insulin resistance: potential links with inflammation. Int J Obes Relat Metab Disord 27(suppl 3):S6–S11. doi: 10.1038/sj.ijo.0802491 PubMedGoogle Scholar
  23. 23.
    Mathis D, Shoelson SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11(2):81. doi: 10.1038/nri2922 PubMedGoogle Scholar
  24. 24.
    Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445. doi: 10.1146/annurev-immunol-031210-101322 PubMedGoogle Scholar
  25. 25.
    Liu G, Yang H (2012) Modulation of macrophage activation and programming in immunity. J Cell Physiol 228(3):502–512. doi: 10.1002/jcp.24157 Google Scholar
  26. 26.
    Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282(48):35279–35292. doi:M706762200[pii].10.1074/jbc.M706762200PubMedGoogle Scholar
  27. 27.
    Lumeng CN, Bodzin JL, Saltiel AR (2007) Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117(1):175–184. doi: 10.1172/JCI29881 PubMedGoogle Scholar
  28. 28.
    Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18(3):363–374. doi:10.1038/nm.2627. nm.2627[pii]PubMedGoogle Scholar
  29. 29.
    Patsouris D, Li PP, Thapar D, Chapman J, Olefsky JM, Neels JG (2008) Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab 8(4):301–309. doi:S1550-4131(08)00282-9[pii].10.1016/j.cmet.2008.08.015PubMedGoogle Scholar
  30. 30.
    Solinas G, Vilcu C, Neels JG, Bandyopadhyay GK, Luo JL, Naugler W, Grivennikov S, Wynshaw-Boris A, Scadeng M, Olefsky JM, Karin M (2007) JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab 6(5):386–397. doi:S1550-4131(07)00292-6[pii].10.1016/j.cmet.2007.09.011PubMedGoogle Scholar
  31. 31.
    Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw-Boris A, Poli G, Olefsky J, Karin M (2005) IKK-beta links inflammation to obesity-induced insulin resistance. Nat Med 11(2):191–198. doi:nm1185[pii].10.1038/nm1185PubMedGoogle Scholar
  32. 32.
    Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447(7148):1116–1120. doi:nature05894[pii].10.1038/nature05894PubMedGoogle Scholar
  33. 33.
    Weisberg SP, Hunter D, Huber R, Lemieux J, Slaymaker S, Vaddi K, Charo I, Leibel RL, Ferrante AW Jr (2006) CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J Clin Invest 116(1):115–124. doi: 10.1172/JCI24335 PubMedGoogle Scholar
  34. 34.
    Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, Kitazawa S, Miyachi H, Maeda S, Egashira K, Kasuga M (2006) MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 116(6):1494–1505. doi: 10.1172/JCI26498 PubMedGoogle Scholar
  35. 35.
    Kosuri M, Bhatnagar A, Jala VR, Haribabu B (2011) Deficiency of the leukotriene B4 receptor, BLT-1, protects against systemic insulin resistance in diet-induced obesity. J Immunol 187(4):1942–1949.­doi: ­doi:10.4049/jimmunol.1100196 PubMedGoogle Scholar
  36. 36.
    Obstfeld AE, Sugaru E, Thearle M, Francisco AM, Gayet C, Ginsberg HN, Ables EV, Ferrante AW Jr (2010) C-C chemokine receptor 2 (CCR2) regulates the hepatic recruitment of myeloid cells that promote obesity-induced hepatic steatosis. Diabetes 59(4):916–925. doi:db09-1403[pii].10.2337/db09-1403PubMedGoogle Scholar
  37. 37.
    Kurihara T, Bravo R (1996) Cloning and functional expression of mCCR2, a murine receptor for the C-C chemokines JE and FIC. J Biol Chem 271(20):11603–11607PubMedGoogle Scholar
  38. 38.
    Charo IF, Myers SJ, Herman A, Franci C, Connolly AJ, Coughlin SR (1994) Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. Proc Natl Acad Sci U S A 91(7):2752–2756PubMedGoogle Scholar
  39. 39.
    Inouye KE, Shi H, Howard JK, Daly CH, Lord GM, Rollins BJ, Flier JS (2007) Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 56(9):2242–2250. doi:db07-0425[pii].10.2337/db07-0425PubMedGoogle Scholar
  40. 40.
    Chen A, Mumick S, Zhang C, Lamb J, Dai H, Weingarth D, Mudgett J, Chen H, MacNeil DJ, Reitman ML, Qian S (2005) Diet induction of monocyte chemoattractant protein-1 and its impact on obesity. Obes Res 13(8):1311–1320. doi: 10.1038/oby.2005.159 PubMedGoogle Scholar
  41. 41.
    Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237(4819):1171–1176PubMedGoogle Scholar
  42. 42.
    Haeggstrom JZ (2004) Leukotriene A4 hydrolase/aminopeptidase, the gatekeeper of chemotactic leukotriene B4 biosynthesis. J Biol Chem 279(49):50639–50642. doi:10.1074/jbc.R400027200. R400027200[pii]PubMedGoogle Scholar
  43. 43.
    Yokomizo T, Izumi T, Chang K, Takuwa Y, Shimizu T (1997) A G-protein-coupled receptor for leukotriene B4 that mediates chemotaxis. Nature 387(6633):620–624. doi: 10.1038/42506 PubMedGoogle Scholar
  44. 44.
    Xu J, Morinaga H, Oh D, Li P, Chen A, Talukdar S, Lazarowski E, Olefsky JM, Kim JJ (2012) GPR105 ablation prevents inflammation and improves insulin sensitivity in mice with diet-induced obesity. J Immunol 189(4):1992–1999. doi:jimmunol.1103207[pii].10.4049/jimmunol.1103207PubMedGoogle Scholar
  45. 45.
    Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ, Watkins SM, Olefsky JM (2010) GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142(5):687–698. doi: 10.1016/j.cell.2010.07.041 PubMedGoogle Scholar
  46. 46.
    Osborn O, da Oh Y, McNelis J, Sanchez-Alavez M, Talukdar S, Lu M, Li P, Thiede L, Morinaga H, Kim JJ, Heinrichsdorff J, Nalbandian S, Ofrecio JM, Scadeng M, Schenk S, Hadcock J, Bartfai T, Olefsky JM (2012) G protein-coupled receptor 21 deletion improves insulin sensitivity in diet-induced obese mice. J Clin Invest 122(7):2444–2453. doi:10.1172/JCI61953. 61953[pii]PubMedGoogle Scholar
  47. 47.
    Gardner J, Wu S, Ling L, Danao J, Li Y, Yeh WC, Tian H, Baribault H (2012) G-protein-coupled receptor GPR21 knockout mice display improved glucose tolerance and increased insulin response. Biochem Biophys Res Commun 418(1):1–5. doi: 10.1016/j.bbrc.2011.11.117 PubMedGoogle Scholar
  48. 48.
    Ichimura A, Hirasawa A, Poulain-Godefroy O, Bonnefond A, Hara T, Yengo L, Kimura I, Leloire A, Liu N, Iida K, Choquet H, Besnard P, Lecoeur C, Vivequin S, Ayukawa K, Takeuchi M, Ozawa K, Tauber M, Maffeis C, Morandi A, Buzzetti R, Elliott P, Pouta A, Jarvelin MR, Korner A, Kiess W, Pigeyre M, Caiazzo R, Van Hul W, Van Gaal L, Horber F, Balkau B, Levy-Marchal C, Rouskas K, Kouvatsi A, Hebebrand J, Hinney A, Scherag A, Pattou F, Meyre D, Koshimizu TA, Wolowczuk I, Tsujimoto G, Froguel P (2012) Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human. Nature 483(7389):350–354. doi: 10.1038/nature10798 PubMedGoogle Scholar
  49. 49.
    Elgazar-Carmon V, Rudich A, Hadad N, Levy R (2008) Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J Lipid Res 49(9):1894–1903. doi:M800132-JLR200[pii].10.1194/jlr.M800132-JLR200PubMedGoogle Scholar
  50. 50.
    Talukdar S, Oh DY, Bandyopadhyay G, Li D, Xu J, McNelis J, Lu M, Li P, Yan Q, Zhu Y, Ofrecio J, Lin M, Brenner MB, Olefsky JM (2012) Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat Med 18(9):1407–1412. ­doi:10.1038/nm.2885. nm.2885[pii]PubMedGoogle Scholar
  51. 51.
    Pham CT (2006) Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6(7):541–550. doi:nri1841[pii].10.1038/nri1841PubMedGoogle Scholar
  52. 52.
    Houghton AM (2010) The paradox of tumor-associated neutrophils: fueling tumor growth with cytotoxic substances. Cell Cycle 9(9):1732–1737. doi:11297[pii]PubMedGoogle Scholar
  53. 53.
    Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE, Stolz DB, Land SR, Marconcini LA, Kliment CR, Jenkins KM, Beaulieu KA, Mouded M, Frank SJ, Wong KK, Shapiro SD (2010) Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med 16(2):219–223. doi:nm.2084[pii].10.1038/nm.2084PubMedGoogle Scholar
  54. 54.
    Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D (2009) Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15(8):930–939. doi:nm.2002[pii].10.1038/nm.2002PubMedGoogle Scholar
  55. 55.
    Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, Dorfman R, Wang Y, Zielenski J, Mastronardi F, Maezawa Y, Drucker DJ, Engleman E, Winer D, Dosch HM (2009) Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15(8):921–929. doi:nm.2001[pii].10.1038/nm.2001 PubMedGoogle Scholar
  56. 56.
    Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D (2012) PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486(7404):549–553. doi:nature11132[pii].10.1038/nature11132 PubMedGoogle Scholar
  57. 57.
    Strissel KJ, DeFuria J, Shaul ME, Bennett G, Greenberg AS, Obin MS (2010) T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver Spring) 18(10):1918–1925. doi:oby20101[pii].10.1038/oby.2010.1 Google Scholar
  58. 58.
    Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T, Nagai R (2009) CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15(8):914–920. doi: 10.1038/nm.1964 PubMedGoogle Scholar
  59. 59.
    Duffaut C, Galitzky J, Lafontan M, Bouloumie A (2009) Unexpected trafficking of immune cells within the adipose tissue during the onset of obesity. Biochem Biophys Res Commun 384(4):482–485. doi: 10.1016/j.bbrc.2009.05.002 PubMedGoogle Scholar
  60. 60.
    Winer DA, Winer S, Shen L, Wadia PP, Yantha J, Paltser G, Tsui H, Wu P, Davidson MG, Alonso MN, Leong HX, Glassford A, Caimol M, Kenkel JA, Tedder TF, McLaughlin T, Miklos DB, Dosch HM, Engleman EG (2011) B cells promote insulin resistance through modulation of T cells and production of pathogenic IgG antibodies. Nat Med 17(5):610–617. doi: 10.1038/nm.2353 PubMedGoogle Scholar
  61. 61.
    Falorni A, Gambelunghe G, Forini F, Kassi G, Cosentino A, Candeloro P, Bolli GB, Brunetti P, Calcinaro F (2000) Autoantibody recognition of COOH-terminal epitopes of GAD65 marks the risk for insulin requirement in adult-onset diabetes mellitus. J Clin Endocrinol Metab 85(1):309–316PubMedGoogle Scholar
  62. 62.
    Gomez-Tourino I, Camina-Darriba F, Otero-Romero I, Rodriguez MA, Hernandez-Fernandez A, Gonzalez-Fernandez A, Pena-Gonzalez E, Rodriguez J, Rodriguez-Segade S, Varela-Calvino R (2010) Autoantibodies to glial fibrillary acid protein and S100beta in diabetic patients. Diabet Med 27(2):246–248. doi: 10.1111/j.1464-5491.2009.02911.x PubMedGoogle Scholar
  63. 63.
    Kotas ME, Lee HY, Gillum MP, Annicelli C, Guigni BA, Shulman GI, Medzhitov R (2011) Impact of CD1d deficiency on metabolism. PLoS One 6(9):e25478. doi:10.1371/journal.pone.0025478.PONE-D-11-12529[pii] PubMedGoogle Scholar
  64. 64.
    Mantell BS, Stefanovic-Racic M, Yang X, Dedousis N, Sipula IJ, O’Doherty RM (2011) Mice lacking NKT cells but with a complete complement of CD8+ T-cells are not protected against the metabolic abnormalities of diet-induced obesity. PLoS One 6(6):e19831. doi:10.1371/journal.pone.0019831.PONE-D-10-04900[pii] PubMedGoogle Scholar
  65. 65.
    Ji Y, Sun S, Xu A, Bhargava P, Yang L, Lam KS, Gao B, Lee CH, Kersten S, Qi L (2012) Activation of natural killer T cells promotes M2 macrophage polarization in adipose tissue and improves systemic glucose tolerance via interleukin-4 (IL-4)/STAT6 protein signaling axis in obesity. J Biol Chem 287(17):13561–13571. doi:M112.350066[pii].10.1074/jbc.M112.350066 PubMedGoogle Scholar
  66. 66.
    Schipper HS, Rakhshandehroo M, van de Graaf SF, Venken K, Koppen A, Stienstra R, Prop S, Meerding J, Hamers N, Besra G, Boon L, Nieuwenhuis EE, Elewaut D, Prakken B, Kersten S, Boes M, Kalkhoven E (2012) Natural killer T cells in adipose tissue prevent insulin resistance. J Clin Invest 122(9):3343–3354. doi:10.1172/JCI62739.62739[pii] PubMedGoogle Scholar
  67. 67.
    Wu D, Molofsky AB, Liang HE, Ricardo-Gonzalez RR, Jouihan HA, Bando JK, Chawla A, Locksley RM (2011) Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis. Science 332(6026):243–247. doi:science.1201475[pii].10.1126/science.1201475 PubMedGoogle Scholar
  68. 68.
    Zhang J, Shi GP (2012) Mast cells and metabolic syndrome. Biochim Biophys Acta 1822(1):14–20. doi:S0925-4439(10)00290-5[pii].10.1016/j.bbadis.2010.12.012 PubMedGoogle Scholar
  69. 69.
    Liu J, Divoux A, Sun J, Zhang J, Clement K, Glickman JN, Sukhova GK, Wolters PJ, Du J, Gorgun CZ, Doria A, Libby P, Blumberg RS, Kahn BB, Hotamisligil GS, Shi GP (2009) Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15(8):940–945. doi:nm.1994[pii].10.1038/nm.1994 PubMedGoogle Scholar
  70. 70.
    Altintas MM, Azad A, Nayer B, Contreras G, Zaias J, Faul C, Reiser J, Nayer A (2011) Mast cells, macrophages, and crown-like structures distinguish subcutaneous from visceral fat in mice. J Lipid Res 52(3):480–488. doi:jlr.M011338[pii].10.1194/jlr.M011338 PubMedGoogle Scholar
  71. 71.
    Divoux A, Moutel S, Poitou C, Lacasa D, Veyrie N, Aissat A, Arock M, Guerre-Millo M, Clement K (2012) Mast cells in human adipose tissue: link with morbid obesity, inflammatory status, and diabetes. J Clin Endocrinol Metab 97(9):E1677–E1685. doi: 10.1210/jc.2012-1532 PubMedGoogle Scholar
  72. 72.
    Gao Z, Hwang D, Bataille F, Lefevre M, York D, Quon MJ, Ye J (2002) Serine phosphorylation of insulin receptor substrate 1 by inhibitor kappa B kinase complex. J Biol Chem 277(50):48115–48121. doi:10.1074/jbc.M209459200.M209459200[pii] PubMedGoogle Scholar
  73. 73.
    Gao Z, Zuberi A, Quon MJ, Dong Z, Ye J (2003) Aspirin inhibits serine phosphorylation of insulin receptor substrate 1 in tumor necrosis factor-treated cells through targeting multiple serine kinases. J Biol Chem 278(27):24944–24950. doi:10.1074/jbc.M300423200.M300423200[pii] PubMedGoogle Scholar
  74. 74.
    Ozes ON, Akca H, Mayo LD, Gustin JA, Maehama T, Dixon JE, Donner DB (2001) A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1. Proc Natl Acad Sci U S A 98(8):4640–4645. doi:10.1073/pnas.051042298.051042298[pii] PubMedGoogle Scholar
  75. 75.
    Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS (2010) Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140(3):338–348. doi:S0092-8674(10)00002-4[pii].10.1016/j.cell.2010.01.001 PubMedGoogle Scholar
  76. 76.
    Tack CJ, Stienstra R, Joosten LA, Netea MG (2012) Inflammation links excess fat to insulin resistance: the role of the interleukin-1 family. Immunol Rev 249(1):239–252. doi: 10.1111/j.1600-065X.2012.01145.x PubMedGoogle Scholar
  77. 77.
    Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286(3):327–334PubMedGoogle Scholar
  78. 78.
    McGillicuddy FC, Harford KA, Reynolds CM, Oliver E, Claessens M, Mills KH, Roche HM (2011) Lack of interleukin-1 receptor I (IL-1RI) protects mice from high-fat diet-induced adipose tissue inflammation coincident with improved glucose homeostasis. Diabetes 60(6):1688–1698. doi: 10.2337/db10-1278 PubMedGoogle Scholar
  79. 79.
    Park E, Wong V, Guan X, Oprescu AI, Giacca A (2007) Salicylate prevents hepatic insulin resistance caused by short-term elevation of free fatty acids in vivo. J Endocrinol 195(2):323–331. doi:195/2/323[pii].10.1677/JOE-07-0005 PubMedGoogle Scholar
  80. 80.
    Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through toll-like receptor 4. J Biol Chem 276(20):16683–16689. doi:10.1074/jbc.M011695200.M011695200[pii] PubMedGoogle Scholar
  81. 81.
    Senn JJ (2006) Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes. J Biol Chem 281(37):26865–26875. doi:M513304200[pii].10.1074/jbc.M513304200 PubMedGoogle Scholar
  82. 82.
    Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116(11):3015–3025. doi: 10.1172/JCI28898 PubMedGoogle Scholar
  83. 83.
    Saberi M, Woods NB, de Luca C, Schenk S, Lu JC, Bandyopadhyay G, Verma IM, Olefsky JM (2009) Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 10(5):419–429. doi:S1550-4131(09)00294-0[pii].10.1016/j.cmet.2009.09.006 PubMedGoogle Scholar
  84. 84.
    Himes RW, Smith CW (2010) Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J 24(3):731–739. doi:fj.09-141929[pii].10.1096/fj.09-141929 PubMedGoogle Scholar
  85. 85.
    Ehses JA, Meier DT, Wueest S, Rytka J, Boller S, Wielinga PY, Schraenen A, Lemaire K, Debray S, Van Lommel L, Pospisilik JA, Tschopp O, Schultze SM, Malipiero U, Esterbauer H, Ellingsgaard H, Rutti S, Schuit FC, Lutz TA, Boni-Schnetzler M, Konrad D, Donath MY (2010) Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet. Diabetologia 53(8):1795–1806. doi: 10.1007/s00125-010-1747-3 PubMedGoogle Scholar
  86. 86.
    Schaeffler A, Gross P, Buettner R, Bollheimer C, Buechler C, Neumeier M, Kopp A, Schoelmerich J, Falk W (2009) Fatty acid-induced induction of toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology 126(2):233–245. doi:IMM2892[pii].10.1111/j.1365-2567.2008.02892.x PubMedGoogle Scholar
  87. 87.
    Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18:1279–1285. doi:10.1038/nm.2851 Google Scholar
  88. 88.
    Mathews ST, Rakhade S, Zhou X, Parker GC, Coscina DV, Grunberger G (2006) Fetuin-null mice are protected against obesity and insulin resistance associated with aging. Biochem Biophys Res Commun 350(2):437–443. doi: 10.1016/j.bbrc.2006.09.071 PubMedGoogle Scholar
  89. 89.
    Heinrichsdorff J, Olefsky JM (2012) Fetuin-A: the missing link in lipid-induced inflammation. Nat Med 18(8):1182–1183. doi: 10.1038/nm.2869 PubMedGoogle Scholar
  90. 90.
    Wong SW, Kwon MJ, Choi AM, Kim HP, Nakahira K, Hwang DH (2009) Fatty acids modulate toll-like receptor 4 activation through regulation of receptor dimerization and recruitment into lipid rafts in a reactive oxygen species-dependent manner. J Biol Chem 284(40):27384–27392. doi:M109.044065[pii].10.1074/jbc.M109.044065 PubMedGoogle Scholar
  91. 91.
    Holzer RG, Park EJ, Li N, Tran H, Chen M, Choi C, Solinas G, Karin M (2011) Saturated fatty acids induce c-Src clustering within membrane subdomains, leading to JNK activation. Cell 147(1):173–184. doi:S0092-8674(11)01004-X[pii].10.1016/j.cell.2011.08.034 PubMedGoogle Scholar
  92. 92.
    Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12(5):408–415. doi: 10.1038/ni.2022 PubMedGoogle Scholar
  93. 93.
    Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR, Pagliassotti MJ, Scherer PE, Summers SA (2011) Lipid-induced insulin resistance mediated by the proinflammatory receptor TLR4 requires saturated fatty acid-induced ceramide biosynthesis in mice. J Clin Invest 121(5):1858–1870. doi: 10.1172/JCI43378 PubMedGoogle Scholar
  94. 94.
    Stratford S, Hoehn KL, Liu F, Summers SA (2004) Regulation of insulin action by ceramide: dual mechanisms linking ceramide accumulation to the inhibition of Akt/protein kinase B. J Biol Chem 279(35):36608–36615. doi: 10.1074/jbc.M406499200 PubMedGoogle Scholar
  95. 95.
    Ussher JR, Koves TR, Cadete VJ, Zhang L, Jaswal JS, Swyrd SJ, Lopaschuk DG, Proctor SD, Keung W, Muoio DM, Lopaschuk GD (2010) Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 59(10):2453–2464. doi: 10.2337/db09-1293 PubMedGoogle Scholar
  96. 96.
    Frangioudakis G, Garrard J, Raddatz K, Nadler JL, Mitchell TW, Schmitz-Peiffer C (2010) Saturated- and n-6 polyunsaturated-fat diets each induce ceramide accumulation in mouse skeletal muscle: reversal and improvement of glucose tolerance by lipid metabolism inhibitors. Endocrinology 151(9):4187–4196. doi: 10.1210/en.2010-0250 PubMedGoogle Scholar
  97. 97.
    Dbaibo GS, El-Assaad W, Krikorian A, Liu B, Diab K, Idriss NZ, El-Sabban M, Driscoll TA, Perry DK, Hannun YA (2001) Ceramide generation by two distinct pathways in tumor necrosis factor alpha-induced cell death. FEBS Lett 503(1):7–12PubMedGoogle Scholar
  98. 98.
    Chavez JA, Summers SA (2012) A ceramide-centric view of insulin resistance. Cell Metab 15(5):585–594. doi: 10.1016/j.cmet.2012.04.002 PubMedGoogle Scholar
  99. 99.
    Hotamisligil GS (2010) Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140(6):900–917. doi:S0092-8674(10)00187-X[pii].10.1016/j.cell.2010.02.034 PubMedGoogle Scholar
  100. 100.
    Engin F, Hotamisligil GS (2010) Restoring endoplasmic reticulum function by chemical chaperones: an emerging therapeutic approach for metabolic diseases. Diabetes Obes Metab 12(suppl 2):108–115. doi: 10.1111/j.1463-1326.2010.01282.x PubMedGoogle Scholar
  101. 101.
    Hu P, Han Z, Couvillon AD, Kaufman RJ, Exton JH (2006) Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Mol Cell Biol 26(8):3071–3084. doi:26/8/3071[pii].10.1128/MCB.26.8.3071-3084.2006 PubMedGoogle Scholar
  102. 102.
    Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding HP, Ron D (2000) Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science 287(5453):664–666. doi:8218[pii] PubMedGoogle Scholar
  103. 103.
    Lee AH, Scapa EF, Cohen DE, Glimcher LH (2008) Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320(5882):1492–1496. doi: 10.1126/science.1158042 PubMedGoogle Scholar
  104. 104.
    Yamamoto K, Takahara K, Oyadomari S, Okada T, Sato T, Harada A, Mori K (2010) Induction of liver steatosis and lipid droplet formation in ATF6alpha-knockout mice burdened with pharmacological endoplasmic reticulum stress. Mol Biol Cell 21(17):2975–2986. doi: 10.1091/mbc.E09-02-0133 PubMedGoogle Scholar
  105. 105.
    Zhang K, Wang S, Malhotra J, Hassler JR, Back SH, Wang G, Chang L, Xu W, Miao H, Leonardi R, Chen YE, Jackowski S, Kaufman RJ (2011) The unfolded protein response transducer IRE1alpha prevents ER stress-induced hepatic steatosis. EMBO J 30(7):1357–1375. doi: 10.1038/emboj.2011.52 PubMedGoogle Scholar
  106. 106.
    Ni M, Lee AS (2007) ER chaperones in mammalian development and human diseases. FEBS Lett 581(19):3641–3651. doi: 10.1016/j.febslet.2007.04.045 PubMedGoogle Scholar
  107. 107.
    Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313(5790):1137–1140. doi: 10.1126/science.1128294 PubMedGoogle Scholar
  108. 108.
    Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, Ferre P, Foufelle F (2009) GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 119(5):1201–1215. doi: 10.1172/JCI37007 PubMedGoogle Scholar
  109. 109.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306(5695):457–461. doi:306/5695/457[pii].10.1126/science.1103160 PubMedGoogle Scholar
  110. 110.
    Ye J, Gao Z, Yin J, He Q (2007) Hypoxia is a potential risk factor for chronic inflammation and adiponectin reduction in adipose tissue of ob/ob and dietary obese mice. Am J Physiol Endocrinol Metab 293(4):E1118–E1128. doi: 10.1152/ajpendo.00435.2007 PubMedGoogle Scholar
  111. 111.
    Pasarica M, Sereda OR, Redman LM, Albarado DC, Hymel DT, Roan LE, Rood JC, Burk DH, Smith SR (2009) Reduced adipose tissue oxygenation in human obesity: evidence for rarefaction, macrophage chemotaxis, and inflammation without an angiogenic response. Diabetes 58(3):718–725. doi: 10.2337/db08-1098 PubMedGoogle Scholar
  112. 112.
    Krishnan J, Danzer C, Simka T, Ukropec J, Walter KM, Kumpf S, Mirtschink P, Ukropcova B, Gasperikova D, Pedrazzini T, Krek W (2012) Dietary obesity-associated Hif1alpha ­activation in adipocytes restricts fatty acid oxidation and energy expenditure via suppression of the Sirt2-NAD+ system. Genes Dev 26(3):259–270. doi: 10.1101/gad.180406.111 PubMedGoogle Scholar
  113. 113.
    Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE (2010) The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann Intern Med 152(6):346–357. doi: 10.1059/0003-4819-152-6-201003160-00004 PubMedGoogle Scholar
  114. 114.
    Rumore MM, Kim KS (2010) Potential role of salicylates in type 2 diabetes. Ann Pharmacother 44(7–8):1207–1221. doi: 10.1345/aph.1M483 PubMedGoogle Scholar
  115. 115.
    Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389(6651):610–614. doi: 10.1038/39335 PubMedGoogle Scholar
  116. 116.
    Grunfeld C, Feingold KR (1991) The metabolic effects of tumor necrosis factor and other cytokines. Biotherapy 3(2):143–158PubMedGoogle Scholar
  117. 117.
    Hotamisligil GS, Murray DL, Choy LN, Spiegelman BM (1994) Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A 91(11):4854–4858PubMedGoogle Scholar
  118. 118.
    Rosenvinge A, Krogh-Madsen R, Baslund B, Pedersen BK (2007) Insulin resistance in patients with rheumatoid arthritis: effect of anti-TNFalpha therapy. Scand J Rheumatol 36(2):91–96. doi: 10.1080/03009740601179605 PubMedGoogle Scholar
  119. 119.
    Stanley TL, Zanni MV, Johnsen S, Rasheed S, Makimura H, Lee H, Khor VK, Ahima RS, Grinspoon SK (2011) TNF-alpha antagonism with etanercept decreases glucose and increases the proportion of high molecular weight adiponectin in obese subjects with features of the metabolic syndrome. J Clin Endocrinol Metab 96(1):E146–E150. doi: 10.1210/jc.2010-1170 PubMedGoogle Scholar
  120. 120.
    Gonzalez-Gay MA, Gonzalez-Juanatey C, Vazquez-Rodriguez TR, Miranda-Filloy JA, Llorca J (2010) Insulin resistance in rheumatoid arthritis: the impact of the anti-TNF-alpha therapy. Ann N Y Acad Sci 1193:153–159. doi:NYAS5287[pii].10.1111/j.1749-6632.2009.05287.x PubMedGoogle Scholar
  121. 121.
    Kiortsis DN, Mavridis AK, Vasakos S, Nikas SN, Drosos AA (2005) Effects of infliximab treatment on insulin resistance in patients with rheumatoid arthritis and ankylosing spondylitis. Ann Rheum Dis 64(5):765–766. doi:10.1136/ard.2004.026534.ard.2004.026534[pii] PubMedGoogle Scholar
  122. 122.
    Yazdani-Biuki B, Stelzl H, Brezinschek HP, Hermann J, Mueller T, Krippl P, Graninger W, Wascher TC (2004) Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti-TNF-alpha antibody infliximab. Eur J Clin Invest 34(9):641–642. doi: 10.1111/j.1365-2362.2004.01390.x PubMedGoogle Scholar
  123. 123.
    Solomon DH, Massarotti E, Garg R, Liu J, Canning C, Schneeweiss S (2011) Association between disease-modifying antirheumatic drugs and diabetes risk in patients with rheumatoid arthritis and psoriasis. JAMA 305(24):2525–2531. doi: 10.1001/jama.2011.878 PubMedGoogle Scholar
  124. 124.
    Osborn O, Brownell SE, Sanchez-Alavez M, Salomon D, Gram H, Bartfai T (2008) Treatment with an interleukin 1 beta antibody improves glycemic control in diet-induced obesity. Cytokine 44(1):141–148. doi: 10.1016/j.cyto.2008.07.004 PubMedGoogle Scholar
  125. 125.
    Larsen CM, Faulenbach M, Vaag A, Volund A, Ehses JA, Seifert B, Mandrup-Poulsen T, Donath MY (2007) Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 356(15):1517–1526. doi: 10.1056/NEJMoa065213 PubMedGoogle Scholar
  126. 126.
    Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107. doi: 10.1038/nri2925 PubMedGoogle Scholar
  127. 127.
    Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA (1995) An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem 270(22):12953–12956PubMedGoogle Scholar
  128. 128.
    Sugii S, Olson P, Sears DD, Saberi M, Atkins AR, Barish GD, Hong SH, Castro GL, Yin YQ, Nelson MC, Hsiao G, Greaves DR, Downes M, Yu RT, Olefsky JM, Evans RM (2009) PPARgamma activation in adipocytes is sufficient for systemic insulin sensitization. Proc Natl Acad Sci U S A 106(52):22504–22509. doi:0912487106[pii].10.1073/pnas.0912487106 PubMedGoogle Scholar
  129. 129.
    Hevener AL, Olefsky JM, Reichart D, Nguyen MT, Bandyopadyhay G, Leung HY, Watt MJ, Benner C, Febbraio MA, Nguyen AK, Folian B, Subramaniam S, Gonzalez FJ, Glass CK, Ricote M (2007) Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones. J Clin Invest 117(6):1658–1669. doi: 10.1172/JCI31561 PubMedGoogle Scholar
  130. 130.
    Hevener AL, He W, Barak Y, Le J, Bandyopadhyay G, Olson P, Wilkes J, Evans RM, Olefsky J (2003) Muscle-specific Pparg deletion causes insulin resistance. Nat Med 9(12):1491–1497. doi:10.1038/nm956.nm956[pii] PubMedGoogle Scholar
  131. 131.
    Ryan KK, Li B, Grayson BE, Matter EK, Woods SC, Seeley RJ (2011) A role for central nervous system PPAR-gamma in the regulation of energy balance. Nat Med 17(5):623–626. doi:nm.2349[pii].10.1038/nm.2349 PubMedGoogle Scholar
  132. 132.
    Lu M, Sarruf DA, Talukdar S, Sharma S, Li P, Bandyopadhyay G, Nalbandian S, Fan W, Gayen JR, Mahata SK, Webster NJ, Schwartz MW, Olefsky JM (2011) Brain PPAR-gamma promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones. Nat Med 17(5):618–622. doi:nm.2332[pii].10.1038/nm.2332 PubMedGoogle Scholar
  133. 133.
    Straus DS, Glass CK (2007) Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol 28(12):551–558. doi: 10.1016/ PubMedGoogle Scholar
  134. 134.
    Cariou B, Zair Y, Staels B, Bruckert E (2011) Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34(9):2008–2014. doi: 10.2337/dc11-0093 PubMedGoogle Scholar
  135. 135.
    Calder PC (2006) n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 83(6 suppl):1505S–1519SPubMedGoogle Scholar
  136. 136.
    Mozaffarian D, Wu JH (2012) (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J Nutr 142(3):614S–625S. doi: 10.3945/jn.111.149633 PubMedGoogle Scholar
  137. 137.
    Renier G, Skamene E, DeSanctis J, Radzioch D (1993) Dietary n-3 polyunsaturated fatty acids prevent the development of atherosclerotic lesions in mice. Modulation of macrophage secretory activities. Arterioscler Thromb 13(10):1515–1524PubMedGoogle Scholar
  138. 138.
    Meydani SN, Endres S, Woods MM, Goldin BR, Soo C, Morrill-Labrode A, Dinarello CA, Gorbach SL (1991) Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women. J Nutr 121(4):547–555PubMedGoogle Scholar
  139. 139.
    Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ (1996) The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr 63(1):116–122PubMedGoogle Scholar
  140. 140.
    Ben-Neriah Y, Karin M (2011) Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol 12(8):715–723. doi:10.1038/[pii] PubMedGoogle Scholar
  141. 141.
    Seki E, Brenner DA, Karin M (2012) A liver full of JNK: signaling in regulation of cell function and disease pathogenesis, and clinical approaches. Gastroenterology 143(2):307–320. doi:S0016-5085(12)00820-7[pii].10.1053/j.gastro.2012.06.004 PubMedGoogle Scholar
  142. 142.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867PubMedGoogle Scholar
  143. 143.
    Gallagher EJ, LeRoith D (2011) Minireview: IGF, insulin, and cancer. Endocrinology 152(7):2546–2551. doi: 10.1210/en.2011-0231 PubMedGoogle Scholar
  144. 144.
    Aaltonen KJ, Virkki LM, Malmivaara A, Konttinen YT, Nordstrom DC, Blom M (2012) Systematic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in treatment of rheumatoid arthritis. PLoS One 7(1):e30275. doi: 10.1371/journal.pone.0030275 PubMedGoogle Scholar
  145. 145.
    van Dartel SA, Fransen J, Kievit W, Flendrie M, den Broeder AA, Visser H, Hartkamp A, van de Laar MA, van Riel PL (2012) Difference in the risk of serious infections in patients with rheumatoid arthritis treated with adalimumab, infliximab and etanercept: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Ann Rheum Dis Published online first: 11 August 2012. doi: 10.1136/annrheumdis-2012-201338
  146. 146.
    Dreyer L, Mellemkjaer L, Andersen AR, Bennett P, Poulsen UE, Juulsgaard Ellingsen T, Hansen TH, Jensen DV, Linde L, Lindegaard HM, Loft AG, Nordin H, Omerovic E, Rasmussen C, Schlemmer A, Tarp U, Hetland ML (2013) Incidences of overall and site ­specific cancers in TNFalpha inhibitor treated patients with rheumatoid arthritis and other arthritides—a follow-up study from the DANBIO Registry. Ann Rheum Dis 72(1):79–82. doi: 10.1136/annrheumdis-2012-201969 PubMedGoogle Scholar
  147. 147.
    Lee RK, Hittel DS, Nyamandi VZ, Kang L, Soh J, Sensen CW, Shearer J (2012) Unconventional microarray design reveals the response to obesity is largely tissue specific: analysis of common and divergent responses to diet-induced obesity in insulin-sensitive tissues. Appl Physiol Nutr Metab 37(2):257–268. doi: 10.1139/h11-159 PubMedGoogle Scholar
  148. 148.
    Chen G, Bentley A, Adeyemo A, Shriner D, Zhou J, Doumatey A, Huang H, Ramos E, Erdos M, Gerry N, Herbert A, Christman M, Rotimi C (2012) Genome-wide association study identifies novel loci association with fasting insulin and insulin resistance in African Americans. Hum Mol Genet 21(20):4530–4536. doi: 10.1093/hmg/dds282 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Lesley G. Ellies
    • 1
  • Andrew Johnson
    • 2
  • Jerrold M. Olefsky
    • 2
    Email author
  1. 1.Department of PathologyUniversity of California, San DiegoLa JollaUSA
  2. 2.Department of Medicine, Division of Endocrinology and MetabolismUniversity of California, San DiegoLa JollaUSA

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