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Obesity, Inflammation, and Insulin Resistance

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Obesity, Inflammation and Cancer

Part of the book series: Energy Balance and Cancer ((EBAC,volume 7))

Abstract

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.

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Abbreviations

ATM:

Adipose tissue macrophage

DIO:

Diet-induced obesity

FFA:

Free fatty acid

GPCR:

G protein-coupled receptor

HFD:

High-fat diet

IL:

Interleukin

SAT:

Subcutaneous adipose tissue

SFA:

Saturated fatty acid

TNF:

Tumor necrosis factor

VAT:

Visceral adipose tissue

WAT:

White adipose tissue

References

  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.2009.2014

    PubMed  CAS  Google Scholar 

  2. Moller DE, Kaufman KD (2005) Metabolic syndrome: a clinical and molecular perspective. Annu Rev Med 56:45–62. doi:10.1146/annurev.med.56.082103.104751

    PubMed  CAS  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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, MD

    Google Scholar 

  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.2011.09.050

    PubMed  CAS  Google Scholar 

  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

    PubMed  Google Scholar 

  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):87–91

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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.2009.08.018

    PubMed  CAS  Google Scholar 

  12. Despres JP, Lemieux I (2006) Abdominal obesity and metabolic syndrome. Nature 444(7121):881–887. doi:10.1038/nature05488

    PubMed  CAS  Google Scholar 

  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):254–260

    PubMed  CAS  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    PubMed  Google Scholar 

  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. 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]

    PubMed  CAS  Google Scholar 

  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.2009-0070

    PubMed  CAS  Google Scholar 

  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. 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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  23. Mathis D, Shoelson SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11(2):81. doi:10.1038/nri2922

    PubMed  CAS  Google Scholar 

  24. Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445. doi:10.1146/annurev-immunol-031210-101322

    PubMed  CAS  Google Scholar 

  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. 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.M706762200

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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.2008.08.015

    PubMed  CAS  Google Scholar 

  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.2007.09.011

    PubMed  CAS  Google Scholar 

  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/nm1185

    PubMed  CAS  Google Scholar 

  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/nature05894

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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/db09-1403

    PubMed  CAS  Google Scholar 

  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):11603–11607

    PubMed  CAS  Google Scholar 

  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):2752–2756

    PubMed  CAS  Google Scholar 

  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/db07-0425

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  41. Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN (1987) Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237(4819):1171–1176

    PubMed  CAS  Google Scholar 

  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]

    PubMed  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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.1103207

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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-JLR200

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  51. Pham CT (2006) Neutrophil serine proteases: specific regulators of inflammation. Nat Rev Immunol 6(7):541–550. doi:nri1841[pii].10.1038/nri1841

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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.2084

    PubMed  CAS  Google Scholar 

  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.2002

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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):309–316

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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):327–334

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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. 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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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):7–12

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  116. Grunfeld C, Feingold KR (1991) The metabolic effects of tumor necrosis factor and other cytokines. Biotherapy 3(2):143–158

    PubMed  CAS  Google Scholar 

  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):4854–4858

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  126. Donath MY, Shoelson SE (2011) Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 11(2):98–107. doi:10.1038/nri2925

    PubMed  CAS  Google Scholar 

  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):12953–12956

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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/j.it.2007.09.003

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  135. Calder PC (2006) n-3 polyunsaturated fatty acids, inflammation, and inflammatory diseases. Am J Clin Nutr 83(6 suppl):1505S–1519S

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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):1515–1524

    PubMed  CAS  Google Scholar 

  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):547–555

    PubMed  CAS  Google Scholar 

  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):116–122

    PubMed  CAS  Google Scholar 

  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/ni.2060.ni.2060[pii]

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  142. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420(6917):860–867

    PubMed  CAS  Google Scholar 

  143. Gallagher EJ, LeRoith D (2011) Minireview: IGF, insulin, and cancer. Endocrinology 152(7):2546–2551. doi:10.1210/en.2011-0231

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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. 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

    PubMed  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

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Acknowledgment

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

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Authors and Affiliations

  1. Department of Pathology, University of California, San Diego, La Jolla, CA, 92093, USA

    Lesley G. Ellies Ph.D.

  2. Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA, 92093, USA

    Andrew Johnson & Jerrold M. Olefsky M.D.

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  1. Lesley G. Ellies Ph.D.
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    Andrew J. Dannenberg

  2. School of Medicine, Center for Science, Health & Society, Case Western Reserve University, Euclid Ave. 10900, Cleveland, 44106, Ohio, USA

    Nathan A. Berger

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Ellies, L.G., Johnson, A., Olefsky, J.M. (2013). Obesity, Inflammation, and Insulin Resistance. In: Dannenberg, A., Berger, N. (eds) Obesity, Inflammation and Cancer. Energy Balance and Cancer, vol 7. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6819-6_1

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