Implication of inflammatory signaling pathways in obesity-induced insulin resistance

Frontiers in Endocrinology

Volumn 3, Issue JAN, 2013, Pages

  Tanti, Jean François ^a,b   Ceppo, Franck ^a,b   Jager, Jennifer ^a,b,c   Berthou, Flavien ^a,b  

^a CENTRE MÉDITERRANÉEN DE MÉDECINE MOLÉCULAIRE C3M   (France)

^b UNIVERSITÉ CÔTE D'AZUR   (France)

^c UNIVERSITY OF PENNSYLVANIA   (United States)

Author keywords

Adipose tissue; Inflammation; Insulin resistance; Macrophages; Obesity; Pattern recognition receptors; Stress kinases

Indexed keywords

EID: 84874247282     PISSN: None     EISSN: 16642392     Source Type: Journal    
DOI: 10.3389/fendo.2012.00181     Document Type: Review

References (133)

1. Amar, J., Chabo, C., Waget, A., Klopp, P., Vachoux, C., Bermudez-Humaran, L. G., et al. (2011). Intestinal mucosal adherence and translocation of commensal bacteria at the early onset of type 2 diabetes: molecular mechanisms and probiotic treatment. EMBO Mol. Med. 3, 559-572.
2. Arkan, M. C., Hevener, A. L., Greten, F. R., Maeda, S., Li, Z. W., Long, J. M., et al. (2005). IKK-beta links inflammation to obesity-induced insulin resistance. Nat. Med. 11, 191-198.
3. Austin, R. L., Rune, A., Bouzakri, K., Zierath, J. R., and Krook, A. (2008). siRNA-mediated reduction of inhibitor of nuclear factor-kappaB kinase prevents tumor necrosis factor-alpha-induced insulin resistance in human skeletal muscle. Diabetes 57, 2066-2073.
4. Banks, A., Li, J., McKeag, L., Hribal, M., Kashiwada, M., Accili, D., et al. (2005). Deletion of SOCS7 leads to enhanced insulin action and enlarged islets of Langerhans. J. Clin. Invest. 115, 2462-2471.
5. Belgardt, B. F., Mauer, J., Wunderlich, F. T., Ernst, M. B., Pal, M., Spohn, G., et al. (2010). Hypothalamic and pituitary c-Jun N-terminal kinase 1 signaling coordinately regulates glucose metabolism. Proc. Natl. Acad. Sci. U.S.A. 107, 6028-6033.
6. Benomar, Y., Berthou, F., Vacher, C. M., Bailleux, V., Gertler, A., Djiane, J., et al. (2009). Leptin but not ciliary neurotrophic factor (CNTF) induces phosphotyrosine phosphatase-1B expression in human neuronal cells (SH-SY5Y): putative explanation of CNTF efficacy in leptin-resistant state. Endocrinology 150, 1182-1191.
7. Bertola, A., Ciucci, T., Rousseau, D., Bourlier, V., Duffaut, C., Bonnafous, S., et al. (2012). Identification of adipose tissue dendritic cells correlated with obesity-associated insulin-resistance and inducing Th17 responses in mice and patients. Diabetes 61, 2238-2247.
8. Bogoyevitch, M. A., and Arthur, P. G. (2008). Inhibitors of c-Jun N-terminal kinases: JuNK no more? Biochim. Biophys. Acta 1784, 76-93.
9. Bost, F., Aouadi, M., Caron, L., Even, P., Belmonte, N., Prot, M., et al. (2005). The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adi-pogenesis. Diabetes 54, 402-411.
10. Boura-Halfon, S., and Zick, Y. (2009). Phosphorylation of IRS proteins, insulin action, and insulin resistance. Am. J. Physiol. Endocrinol. Metab. 296, E581-E591.
11. Bouzakri, K., Roques, M., Gual, P., Espinosa, S., Guebre-Egziabher, F., Riou, J. P., et al. (2003). Reducedactivation of phosphatidylinositol-3 kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 52, 1319-1325.
12. Burcelin, R., Serino, M., Chabo, C., Blasco-Baque, V., and Amar, J. (2011). Gut microbiota and diabetes: from pathogenesis to therapeutic perspective. Acta Diabetol. 48, 257-273.
13. Cai, D., Yuan, M., Frantz, D. F., Melendez, P. A., Hansen, L., Lee, J., et al. (2005). Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat. Med. 11, 183-190.
14. Cani, P. D., and Delzenne, N. M. (2009). The role of the gut micro-biota in energy metabolism and metabolic disease. Curr. Pharm. Des. 15, 1546-1558.
15. Caricilli, A., Picardi, P., de Abreu, L. L., Ueno, M., Prada, P., Ropelle, E., et al. (2011). Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol. 9:e1001212. doi: 10.1371/jour-nal.pbio.1001212
16. Caricilli, A. M., Nascimento, P. H., Pauli, J. R., Tsukumo, D. M., Velloso, L. A., Carvalheira, J. B., et al. (2008). Inhibition of toll-like receptor 2expression improves insulin sensitivity and signaling in muscle and white adipose tissue of mice fed a high-fat diet. J. Endocrinol. 199, 399-406.
17. Cho, H., Black, S. C., Looper, D., Shi, M., Kelly-Sullivan, D., Timofeevski, S., et al. (2008). Pharmacological characterization of a small molecule inhibitor of c-Jun kinase. Am. J. Physiol. Endocrinol. Metab. 295, E1142-E1151.
18. Cnop, M., Foufelle, F., and Velloso, L. A. (2011). Endoplasmic reticulum stress, obesity and diabetes. Tr e n d s Mol. Med. 18, 59-68.
19. Coenen, K., Gruen, M., Lee-Young, R., Puglisi, M., Wasserman, D., and Hasty, A. (2009). Impact of macrophage toll-like receptor 4 deficiency on macrophage infiltration into adipose tissue and the artery wall in mice. Diabetologia 52, 318-328.
20. Copps, K. D., and White, M. F. (2012). Regulation of insulin sensitivity by serine/threonine phos-phorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 55, 2565-2582.
21. Davis, J. E., Gabler, N. K., Walker-Daniels, J., and Spurlock, M. E. (2008). Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity (Silver Spring) 16, 1248-1255.
22. Ding, Y., Subramanian, S., Montes, V., Goodspeed, L., Wang, S., Han, C., et al. (2012). Toll-like receptor 4 deficiency decreases atherosclerosis but does not protect against inflammation in obese low-density lipoprotein receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 32, 1596-1604.
23. Donath, M. Y., and Shoelson, S. E. (2011). Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98-107.
24. Dumitru, C. D., Ceci, J. D., Tsatsanis, C., Kontoyiannis, D., Stamatakis, K., Lin, J. H., et al. (2000). TNF-alpha induction by LPS is regulated posttranscriptionally via a Tpl2/ERK-dependent pathway. Cell 103, 1071-1083.
25. Ehses, J., Meier, D., Wueest, S., Rytka, J., Boller, S., Wielinga, P., et al. (2010). Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet. Diabetologia 53, 1795-1806.
26. Emanuelli, B., Eberle, D., Suzuki, R., and Kahn, C. R. (2008a). Overexpression of the dual-specificityphosphatase MKP-4/DUSP-9 protects against stress-induced insulin resistance. Proc. Natl. Acad. Sci. U.S.A. 105, 3545-3550.
27. Emanuelli, B., Macotela, Y., Boucher, J., and Ronald Kahn, C. (2008b). SOCS-1 deficiency does not prevent diet-induced insulin resistance. Biochem. Biophys. Res. Commun. 377, 447-452.
28. Emanuelli, B., Peraldi, P., Filloux, C., Sawka-Verhelle, D., Hilton, D., and Van Obberghen, E. (2000). SOCS-3 is an insulin-induced negative regulator of insulin signaling. J. Biol. Chem. 275, 15985-15991.
29. Erridge, C., and Samani, N. J. (2009). Saturated fatty acids do not directly stimulate Toll-like receptor signaling. Arterioscler. Thromb. Vasc. Biol. 29, 1944-1949.
30. Fischer, H., Ellstrom, P., Ekstrom, K., Gustafsson, L., Gustafsson, M., and Svanborg, C. (2007). Ceramide as a TLR4 agonist; a putative signalling intermediate between sphingolipid receptors for microbial ligands and TLR4. Cell. Microbiol. 9, 1239-1251.
31. Flamment, M., Hajduch, E., Ferre, P., and Foufelle, F. (2012). New insights into ER stress-induced insulin resistance. Trends Endocrinol. Metab. 23, 381-390.
32. Fresno, M., Alvarez, R., and Cuesta, N. (2011). Toll-like receptors, inflammation, metabolism and obesity. Arch. Physiol. Biochem. 117, 151-164.
33. Gantke, T., Sriskantharajah, S., and Ley, S. C. (2011). Regulation and function of TPL-2, an IkB kinase-regulated MAP kinase kinase kinase. Cell Res. 21, 131-145.
34. Goldfine, A. B., Fonseca, V., Jablonski, K. A., Pyle, L., Staten, M. A., and Shoelson, S. E. (2010). The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Ann. Intern. Med. 152, 346-357.
35. Gregor, M. F., and Hotamisligil, G. S. (2011). Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415-445.
36. Gual, P., Le Marchand-Brustel, Y., and Tanti, J. F. (2005). Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 87, 99-109.
37. Gurcel, L., Abrami, L., Girardin, S., Tschopp, J., and van der Goot, F. G. (2006). Caspase-1 activation of lipid metabolic pathways in response to bacterial pore-forming toxins promotes cell survival. Cell 126, 1135-1145.
38. Himes, R., and Smith, C. (2010). Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J. 24, 731-739.
39. Hirosumi, J., Tuncman, G., Chang, L., Gorgun, C. Z., Uysal, K. T., Maeda, K., et al. (2002). A central role for JNK in obesity and insulin resistance. Nature 420, 333-336.
40. Howard, J. K., Cave, B. J., Oksanen, L. J., Tzameli, I., Bjorbaek, C., and Flier, J. S. (2004). Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with hap-loinsufficiency of Socs3. Nat. Med. 10, 734-738.
41. Im, S. S., Yousef, L., Blaschitz, C., Liu, J. Z., Edwards, R. A., Young, S. G., et al. (2011). Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab. 13, 540-549.
42. Jager, J., Corcelle, V., Gremeaux, T., Laurent, K., Waget, A., Pages, G., et al. (2011). Deficiency in the extracellular signal-regulated kinase 1 (ERK1) protects leptin-deficient mice from insulin resistance without affecting obesity. Diabetologia 54, 180-189.
43. Jager, J., Gremeaux, T., Cormont, M.,LeMarchand-Brustel, Y., and Tanti, J. F. (2007). Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 148, 241-251.
44. Jager, J., Gremeaux, T., Gonzalez, T., Bonnafous, S., Debard, C.,Laville, M., et al. (2010). The Tpl2 kinase is up-regulated in adipose tissue in obesity and may mediate IL-1(Minamino et al.) and TNF-(alpha) effects on ERK activation and lipolysis. Diabetes 59, 61-70.
45. Jamieson, E., Chong, M., Steinberg, G., Jovanovska, V., Fam, B., Bullen, D., et al. (2005). Socs1 deficiency enhances hepatic insulin signaling. J. Biol. Chem. 280, 31516-31521.
46. Jiao, P., Feng, B., Ma, J., Nie, Y., Paul, E., Li, Y., et al. (2012). Constitutive activation of IKKbeta in adipose tissue prevents diet-induced obesity in mice. Endocrinology 153, 154-165.
47. Jorgensen, S., O'Neill, H., Sylow, L., Honeyman, J., Hewitt, K., Palanivel, R., et al. (2012). Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. Diabetes 62, 56-64.
48. Kaddai, V., Jager, J., Gonzalez, T., Najem-Lendom, R., Bonnafous, S., Tran, A., et al. (2009). Involvement of TNF-alpha in abnormal adipocyte and muscle sortilin expression in obese mice and humans. Diabetologia 52, 932-940.
49. Keshet, Y., and Seger, R. (2010). The MAP kinase signaling cascades: a system of hundreds of components regulates a diverse array of physiological functions. Methods Mol. Biol. 661, 3-38.
50. Kievit, P., Howard, J., Badman, M., Balthasar, N., Coppari, R., Mori, H., et al. (2006). Enhanced lep-tin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells. Cell Metab. 4, 123-132.
51. Kim, F., Pham, M., Luttrell, I., Bannerman, D. D., Tupper, J., Thaler, J., et al. (2007). Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ. Res. 100, 1589-1596.
52. Kleinridders, A., Schenten, D., Könner, A., Belgardt, B., Mauer, J., Okamura, T., et al. (2009). MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab. 10, 249-259.
53. Koenen, T. B., Stienstra, R., van Tits, L. J., Joosten, L. A., van Velzen, J. F., Hijmans, A., et al. (2011). The inflammasome and caspase-1 activation: a new mechanism underlying increased inflammatory activity in human visceral adipose tissue. Endocrinology 152, 3769-3778.
54. Könner, A., and Brüning, J. (2011). Toll-like receptors: linking inflammation to metabolism. Trends Endocrinol. Metab. 22, 16-23.
55. Koska, J., Ortega, E., Bunt, J. C., Gasser, A., Impson, J., Hanson, R. L., et al. (2009). The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomised double-blind placebo-controlled study. Diabetologia 52, 385-393.
56. Kuo, L. H., Tsai, P. J., Jiang, M. J., Chuang, Y. L., Yu, L., Lai, K. T. A., et al. (2011). Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse. Diabetologia 54, 168-179.
57. Lagathu, C., Yvan-Charvet, L., Bastard, J. P., Maachi, M., Quignard-Boulange, A., Capeau, J., et al. (2006). Long-term treatment with interleukin-1beta induces insulin resistance in murine and human adipocytes. Diabetologia 49, 2162-2173.
58. Lancaster, G. I., Kowalski, G. M., Estevez, E., Kraakman, M. J., Grigoriadis, G., Febbraio, M. A., et al. (2012). Tumor progression locus 2 (Tpl2) deficiency does not protect against obesity-induced metabolic disease. PLoS ONE 7:e39100. doi: 10.1371/journal.pone.0039100
59. Larsen, C. M., Faulenbach, M., Vaag, A., Volund, A., Ehses, J. A., Seifert, B., et al. (2007). Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N. Engl. J. Med. 356, 1517-1526.
60. Lebrun, P., Cognard, E., Bellon-Paul, R., Gontard, P., Filloux, C., Jehl-Pietri, C., et al. (2009). Constitutive expression of suppressor of cytokine signalling-3 in skeletal muscle leads to reduced mobility and overweight in mice. Diabetologia 52, 2201-2212.
61. Lebrun, P., and Van Obberghen, E. (2008). SOCS proteins causing trouble in insulin action. Acta Physiol. (Oxf.) 192, 29-36.
62. Lee, D. F., Kuo, H. P., Chen, C. T., Wei, Y., Chou, C. K., Hung, J. Y., et al. (2008). IKKbeta suppression of TSC1 function links the mTOR pathway with insulin resistance. Int. J. Mol. Med. 22, 633-638.
63. Lee, S. J., Pfluger, P. T., Kim, J. Y., Nogueiras, R., Duran, A., Pages, G., et al. (2010). A functional role for the p62-ERK1 axis in the control of energy homeostasis and adipogenesis. EMBO Rep. 11, 226-232.
64. Li, L., Chen, L., Hu, L., Liu, Y., Sun, H.-Y., Tang, J., et al. (2011). Nuclear factor high-mobility group box1 mediating the activation of Toll-like receptor 4 signaling in hepatocytes in the early stage ofnonalcoholic fatty liver disease in mice. Hepatology 54, 1620-1630.
65. Li, L., Grønning, L., Anderson, P., Li, S., Edvardsen, K., Johnston, J., et al. (2004). Insulin induces SOCS-6 expression and its binding to the p85 monomer of phosphoinositide 3-kinase, resulting in improvement in glucose metabolism. J. Biol. Chem. 279, 34107-34114.
66. Lolmede, K., Duffaut, C., Zakaroff-Girard, A., and Bouloumie, A. (2011). Immune cells in adipose tissue: key players in metabolic disorders. Diabetes Metab. 37, 283-290.
67. Milanski, M., Degasperi, G., Coope, A., Morari, J., Denis, R., Cintra, D., et al. (2009). Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypotha-lamus: implications for the patho-genesis of obesity. J. Neurosci. 29, 359-370.
68. Mogensen, T. H. (2009). Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 22, 240-273.
69. Mori, H., Hanada, R., Hanada, T., Aki, D., Mashima, R., Nishinakamura, H., et al. (2004). Socs3 deficiency in the brain elevates leptin sensitivity and confers resistance to diet-induced obesity. Nat. Med. 10, 739-743.
70. Nakamura, T., Furuhashi, M., Li, P., Cao, H., Tuncman, G., Sonenberg, N., et al. (2010). Double-stranded RNA-dependent protein kinase links pathogen sensing with stress and metabolic homeostasis. Cell 140, 338-348.
71. Nicholson, J. K., Holmes, E., Kinross, J., Burcelin, R., Gibson, G., Jia, W., et al. (2012). Host-gut microbiota metabolic interactions. Science 336, 1262-1267.
72. Orr, J., Puglisi, M., Ellacott, K., Lumeng, C., Wasserman, D., and Hasty, A. (2012). Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages. Diabetes 61, 2718-2727.
73. Oslowski, C. M., Hara, T., O'Sullivan-Murphy, B., Kanekura, K., Lu, S., Hara, M., et al. (2012). Thioredoxin-interactingpro-tein mediates ER stress-induced beta cell death through initiation of the inflammasome. Cell Metab. 16, 265-273.
74. Ozcan, U., Cao, Q., Yilmaz, E., Lee, A. H., Iwakoshi, N. N., Ozdelen, E., et al. (2004). Endoplasmic retic-ulum stress links obesity, insulin action, and type 2 diabetes. Science 306, 457-461.
75. Ozcan, U., Ozcan, L., Yilmaz, E., Duvel, K., Sahin, M., Manning, B. D., et al. (2008). Loss of the tuberous sclerosis complex tumor suppressors triggers the unfolded protein response to regulate insulin signaling and apoptosis. Mol. Cell 29, 541-551.
76. Pal, D., Dasgupta, S., Kundu, R., Maitra, S., Das, G., Mukhopadhyay, S., et al. (2012). Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279-1285.
77. Palanivel, R., Fullerton, M., Galic, S., Honeyman, J., Hewitt, K., Jorgensen, S., et al. (2012). Reduced Socs3 expression in adipose tissue protects female mice against obesity-induced insulin resistance. Diabetologia 55, 3083-3093.
78. Perfield, J. W. 2nd., Lee, Y., Shulman, G. I., Samuel, V. T., Jurczak, M. J., Chang, E., et al. (2011). Tumor progression locus 2 (TPL2) regulates obesity-associated inflammation and insulin resistance. Diabetes 60, 1168-1176.
79. Poggi, M., Bastelica, D., Gual, P., Iglesias, M., Gremeaux, T., Knauf, C., et al. (2007). C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50, 1267-1276.
80. Poggi, M., Jager, J., Paulmyer-Lacroix, O., Peiretti, F., Gremeaux, T., Verdier, M., et al. (2009). The inflammatory receptor CD40 is expressed on human adipocytes: contribution to crosstalk between lymphocytes and adipocytes. Diabetologia 52, 1152-1163.
81. Radin, M., Sinha, S., Bhatt, B., Dedousis, N., and O'Doherty, R. (2008). Inhibition or deletion of the lipopolysaccharide receptor Toll-like receptor-4 confers partial protection against lipid-induced insulin resistance in rodent skeletal muscle. Diabetologia 51, 336-346.
82. Regazzetti, C., Peraldi, P., Gremeaux, T., Najem-Lendom, R., Ben-Sahra, I., Cormont, M., et al. (2009). Hypoxia decreases insulin signaling pathways in adipocytes. Diabetes 58, 95-103.
83. Rieusset, J., Bouzakri, K., Chevillotte, E., Ricard, N., Jacquet, D., Bastard, J. P., et al. (2004). Suppressor of cytokine signaling 3 expression and insulin resistance in skeletal muscle of obese and type 2 diabetic patients. Diabetes 53, 2232-2241.
84. Rodriguez, A., Duran, A., Selloum, M., Champy, M.-F., Diez-Guerra, F. J., Flores, J. M., et al. (2006). Mature-onset obesity and insulin resistancein mice deficient in the signaling adapter p62. Cell Metab. 3, 211-222.
85. Rohl, M., Pasparakis, M., Baudler, S., Baumgartl, J., Gautam, D., Huth, M., et al. (2004). Conditional disruption of IkappaB kinase 2 fails to prevent obesity-induced insulin resistance. J. Clin. Invest. 113, 474-481.
86. Saberi, M., Woods, N. B., de Luca, C., Schenk, S., Lu, J. C., Bandyopadhyay, G., et al. (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, 419-429.
87. Sabio, G., Cavanagh-Kyros, J., Barrett, T., Jung, D. Y., Ko, H. J., Ong, H., et al. (2010a). Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1. Genes Dev. 24, 256-264.
88. Sabio, G., Kennedy, N. J., Cavanagh-Kyros, J., Jung, D. Y., Ko, H. J., Ong, H., et al. (2010b). Role of muscle c-Jun NH2-terminal kinase 1 in obesity-induced insulin resistance. Mol. Cell. Biol. 30, 106-115.
89. Sabio, G., Cavanagh-Kyros, J., Ko, H. J., Jung, D. Y., Gray, S., Jun, J. Y., et al. (2009). Prevention of steato-sis by hepatic JNK1. Cell Metab. 10, 491-498.
90. Sabio, G., Das, M., Mora, A., Zhang, Z., Jun, J. Y., Ko, H. J., et al. (2008). A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539-1543.
91. Sabio, G., and Davis, R. J. (2010). cJun NH2-terminal kinase 1 (JNK1): roles in metabolic regulation of insulin resistance. TrendsBiochem. Sci. 35, 490-496.
92. Sachithanandan, N., Fam, B., Fynch, S., Dzamko, N., Watt, M., Wormald, S., et al. (2010). Liver-specific suppressor of cytokine signaling-3 deletion in mice enhances hepatic insulin sensitivity and lipogenesis resulting in fatty liver and obesity. Hepatology 52, 1632-1642.
93. Sachithanandan, N., Graham, K., Galic, S., Honeyman, J., Fynch, S., Hewitt, K., et al. (2011). Macrophage deletion of SOCS1 increases sensitivity to LPS and palmitic acid and results in systemic inflammation and hepatic insulin resistance. Diabetes 60, 2023-2031.
94. Schertzer, J. D., Tamrakar, A. K., Magalhaes, J. G., Pereira, S., Bilan, P. J., Fullerton, M. D., et al. (2011). NOD1 activators link innate immunity to insulin resistance. Diabetes 60, 2206-2215.
95. Shi, H., Cave, B., Inouye, K., Bjorbaek, C., and Flier, J. S. (2006a). Overexpression of suppressorof cytokine signaling 3 in adipose tissue causes local but not systemic insulin resistance. Diabetes 55, 699-707.
96. Shi, H., Kokoeva, M., Inouye, K., Tzameli, I., Yin, H., and Flier, J. (2006b). TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015-3025.
97. Solinas, G., and Karin, M. (2010). JNK1 and IKKbeta: molecular links between obesity and metabolic dysfunction. FASEB J. 24, 2596-2611.
98. Solinas, G., Vilcu, C., Neels, J. G., Bandyopadhyay, G. K., Luo, J. L., Naugler, W., et al. (2007). JNK1 in hematopoietically derived cells contributes to diet-induced inflammation and insulin resistance without affecting obesity. Cell Metab. 6, 386-397.
99. Souza, S. C., Palmer, H. J., Kang, Y. H., Yamamoto, M. T., Muliro, K. V., Paulson, K. E., et al. (2003). TNF-alpha induction of lipolysis is mediated through activation of the extracellular signal related kinase pathway in 3T3-L1 adipocytes. J. Cell. Biochem. 89, 1077-1086.
100. Stienstra, R., Joosten, L. A., Koenen, T., van Tits, B., van Diepen, J. A., van den Berg, S. A., et al. (2010). The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab. 12, 593-605.
101. Stienstra, R., van Diepen, J. A., Tack, C. J., Zaki, M. H., van de Veerdonk, F. L., Perera, D., et al. (2011). Inflammasome is a central player in the induction of obesity and insulin resistance. Proc. Natl. Acad. Sci. U.S.A. 108, 15324-15329.
102. Suganami, T., Mieda, T., Itoh, M., Shimoda, Y., Kamei, Y., and Ogawa, Y. (2007a). Attenuation of obesity-induced adipose tissue inflammation in C3H/HeJ mice carrying a Toll-like receptor 4 mutation. Biochem. Biophys. Res. Commun. 354, 45-49.
103. Suganami, T., Tanimoto-Koyama, K., Nishida, J., Itoh, M., Yuan, X., Mizuarai, S., et al. (2007b). Role of the Toll-like receptor 4/NF-kappaB pathway in saturated fatty acid-induced inflammatory changes in the interaction between adipocytes and macrophages. Arterioscler. Thromb. Vasc. Biol. 27, 84-91.
104. Sun, S., Ji, Y., Kersten, S., and Qi, L. (2012). Mechanisms of inflammatory responses in obese adipose tissue. Annu. Rev. Nutr. 32, 261-286.
105. Symons, A., Beinke, S., and Ley, S. C. (2006). MAP kinase kinase kinases and innate immunity. Trends Immunol. 27, 40-48.
106. Tamrakar, A. K., Schertzer, J. D., Chiu, T. T., Foley, K. P., Bilan, P. J., Philpott, D. J., et al. (2010). NOD2 activation induces muscle cell-autonomous innate immune responses and insulin resistance. Endocrinology 151, 5624-5637.
107. Tamura, Y., Ogihara, T., Uchida, T., Ikeda, F., Kumashiro, N., Nomiyama, T., et al. (2007). Amelioration of glucose tolerance by hepatic inhibition of nuclear factor kappaB in db/db mice. Diabetologia 50, 131-141.
108. Taniguchi, C. M., Emanuelli, B., and Kahn, C. R. (2006). Critical nodes in signalling pathways: insights into insulin action. Nat. Rev. Mol. Cell Biol. 7, 85-96.
109. Tanti, J. F., Gremeaux, T., van Obberghen, E., and Le Marchand-Brustel, Y. (1994). Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. J. Biol. Chem. 269, 6051-6057.
110. Tanti, J. F., and Jager, J. (2009). Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phospho-rylation. Curr. Opin. Pharmacol. 9, 753-762.
111. Torisu, T., Sato, N., Yoshiga, D., Kobayashi, T., Yoshioka, T., Mori, H., et al. (2007). The dual function of hepatic SOCS3 in insulin resistance in vivo. Genes Cells 12, 143-154.
112. Triantafilou, M., Gamper, F. G., Haston, R. M., Mouratis, M. A., Morath, S., Hartung, T., et al. (2006). Membrane sorting of toll-like receptor (TLR)-2/6 and TLR2/1 heterodimers at the cell surface determines heterotypic associations with CD36 and intra-cellular targeting. J. Biol. Chem. 281, 31002-31011.
113. Tschopp, J., and Schroder, K. (2010). NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROSproduction? Nat. Rev. Immunol. 10, 210-215.
114. Tsukumo, D., Carvalho-Filho, M., Carvalheira, J., Prada, P. C., Hirabara, S., Schenka, A., et al. (2007). Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56, 1986-1998.
115. Tuncman, G., Hirosumi, J., Solinas, G., Chang, L., Karin, M., and Hotamisligil, G. S. (2006). Functional in vivo interactions between JNK1 and JNK2 isoforms in obesity and insulin resistance. Proc. Natl. Acad. Sci. U.S.A. 103, 10741-10746.
116. Ueki, K., Kadowaki, T., and Kahn, C. R. (2005). Role of suppressors of cytokine signaling SOCS-1 and SOCS-3 in hepatic steatosis and the metabolic syndrome. Hepatol. Res. 33, 185-192.
117. Vallerie, S. N., Furuhashi, M., Fucho, R., and Hotamisligil, G. S. (2008). A predominant role for parenchymal c-Jun amino terminal kinase (JNK) in the regulation of systemic insulin sensitivity. PLoS ONE 3:e3151. doi: 10.1371/journal.pone.0003151
118. Vandanmagsar, B., Youm, Y. H., Ravussin, A., Galgani, J. E., Stadler, K., Mynatt, R. L., et al. (2011). The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat. Med. 17, 179-188.
119. van Diepen, J. A., Wong, M. C., Guigas, B., Bos, J., Stienstra, R., Hodson, L., et al. (2011). Hepatocyte-specific IKK-beta activation enhances VLDL-triglyceride production in APOE*3-Leiden mice. J. Lipid Res. 52, 942-950.
120. Vijay-Kumar, M., Aitken, J., Carvalho, F., Cullender, T., Mwangi, S., Srinivasan, S., et al. (2010). Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science 328, 228-231.
121. Wen, H., Gris, D., Lei, Y., Jha, S., Zhang, L., Huang, M. T., et al. (2011). Fatty acid-induced NLRP3-ASC inflam-masome activation interferes withinsulin signaling. Nat. Immunol. 12, 408-415.
122. Wood, I. S., de Heredia, F. P., Wang, B., and Trayhurn, P. (2009). Cellular hypoxia and adipose tissue dysfunction in obesity. Proc. Nutr. Soc. 68, 370-377.
123. Wunderlich, F. T., Luedde, T., Singer, S., Schmidt-Supprian, M., Baumgartl, J., Schirmacher, P., et al. (2008). Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but syn-ergizes with high-fat feeding in tumorigenesis. Proc. Natl. Acad. Sci. U.S.A. 105, 1297-1302.
124. Xu, C., Bailly-Maitre, B., and Reed, J. C. (2005). Endoplasmic reticulum stress: cell life and death decisions. J. Clin. Invest. 115, 2656-2664.
125. Yang, R., and Trevillyan, J. M. (2008). c-Jun N-terminal kinase pathways in diabetes. Int. J. Biochem. Cell Biol. 40, 2702-2706.
126. Ye, D., Li, F., Lam, K., Li, H., Jia, W., Wang, Y., et al. (2012). Tolllike receptor-4 mediates obesity-induced non-alcoholic steatohep-atitis through activation of X-box binding protein-1 in mice. Gut 61, 1058-1067.
127. Yuan, M., Konstantopoulos, N., Lee, J., Hansen, L., Li, Z. W., Karin, M., et al. (2001). Reversal of obesity-and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta. Science 293, 1673-1677.
128. Zabolotny, J. M., Kim, Y. B., Welsh, L. A., Kershaw, E. E., Neel, B. G., and Kahn, B. B. (2008). Protein-tyrosine phosphatase 1B expression is induced by inflammation in vivo. J. Biol. Chem. 283, 14230-14241.
129. Zadjali, F., Santana-Farre, R., Vesterlund, M., Carow, B., Mirecki-Garrido, M., Hernandez-Hernandez, I., et al. (2012). SOCS2 deletion protects against hepatic steatosis but worsens insulin resistance in high-fat-diet-fed mice. FASEB J. 26, 3282-3291.
130. Zhang, X., Xu, A., Chung, S. K., Cresser, J. H., Sweeney, G., Wong, R. L., et al.(2011). Selective inactivation of c-Jun NH2-terminal kinase in adipose tissue protects against diet-induced obesity and improves insulin sensitivity in both liver and skeletal muscle in mice. Diabetes 60, 486-495.
131. Zhang, X., Zhang, G., Zhang, H., Karin, M., Bai, H., and Cai, D. (2008). Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135, 61-73.
132. Zhao, L., Hu, P., Zhou, Y., Purohit, J., and Hwang, D. (2011). NOD1 activation induces proinflammatory gene expression and insulin resistance in 3T3-L1 adipocytes. Am. J. Physiol. Endocrinol. Metab. 301, E587-E598.
133. Zhou, R., Tardivel, A., Thorens, B., Choi, I., and Tschopp, J. (2010). Thioredoxin-interacting protein links oxidative stress to inflamma-some activation. Nat. Immunol. 11, 136-140.