Obesity-driven gut microbiota inflammatory pathways to metabolic syndrome

Frontiers in Physiology

Volumn 6, Issue NOV, 2015, Pages

  Cavalcante Silva, Luiz H A ^a   Galvão, José G F M ^a   da Silva, Juliane Santos de França ^a   de Sales Neto, José M ^a   Rodrigues Mascarenhas, Sandra ^a  

^a FEDERAL UNIVERSITY OF PARAÍBA   (Brazil)

Author keywords

Adipose tissue; Cytokines; Gut microbiota; Immune system; Toll like receptors

Indexed keywords

I KAPPA B KINASE BETA; PHOSPHATIDYLINOSITOL 3 KINASE; STRESS ACTIVATED PROTEIN KINASE; TOLL LIKE RECEPTOR; TOLL LIKE RECEPTOR 4;

ADIPOSE TISSUE; CELL FUNCTION; CELL INFILTRATION; CYTOKINE PRODUCTION; DISEASE ASSOCIATION; GENE EXPRESSION REGULATION; HOST PATHOGEN INTERACTION; HUMAN; IMMUNE DEFICIENCY; IMMUNOMODULATION; INNATE IMMUNITY; INSULIN RESISTANCE; INSULIN SENSITIVITY; INTESTINE FLORA; METABOLIC SYNDROME X; NONHUMAN; OBESITY; PATHOGENESIS; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION;

EID: 84949565086     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2015.00341     Document Type: Review

References (187)

1. Aderem, A., and Ulevitch, R. J. (2000). Toll-like receptors in the induction of the innate immune response. Nature 406, 782-787. doi: 10.1038/35021228.
2. Akira, S., Uematsu, S., and Takeuchi, O. (2006). Pathogen recognition and innate immunity. Cell 124, 783-801. doi: 10.1016/j.cell.2006.02.015.
3. Alexopoulou, L., Holt, A. C., Medzhitov, R., and Flavell, R. A. (2001). Recognition of double-stranded RNA and activation of NF-γB by toll-like receptor 3. Nature 413, 732-738. doi: 10.1038/35099560.
4. Amano, S. U., Cohen, J. L., Vangala, P., Tencerova, M., Nicoloro, S. M., Yawe, J. C., et al. (2014). Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 19, 162-172. doi: 10.1016/j.cmet.2013.11.017.
5. Andreasen, A. S., Larsen, N., Pedersen-Skovsgaard, T., Berg, R. M., Møller, K., Svendsen, K. D., et al. (2010). Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects. Br. J. Nutr. 104, 1831-1838. doi: 10.1017/S0007114510002874.
6. 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.
7. Aronsson, L., Huang, Y., Parini, P., Korach-André, M., Håkansson, J., Gustafsso, J., et al. (2010). Decreased fat storage by Lactobacillus paracasei is associated with increased levels of angiopoietin-like 4 protein (ANGPTL4). PLoS ONE 5:e13087. doi: 10.1371/journal.pone.0013087.
8. Ashley, N. T., Weil, Z. M., and Nelson, R. J. (2012). Inflammation: mechanisms, costs, and natural variation. Annu. Rev. Ecol. Evol. Syst. 43, 385-406. doi: 10.1146/annurev-ecolsys-040212-092530.
9. Bäckhed, F., Ding, H., Wang, T., Hooper, L. V., Koh, G. Y., Nagy, A., et al. (2004). The gut microbiota as an environmental factor that regulates fat storage. Proc. Natl. Acad. Sci. U.S.A. 101, 15718-15723. doi: 10.1073/pnas.0407076101.
10. Bäckhed, F., Ley, R. E., Sonnenburg, J. L., Peterson, D. A., and Gordon, J. I. (2005). Host-bacterial mutualism in the human intestine. Science. 307, 1915-1920. doi: 10.1126/science.1104816.
11. Bäckhed, F., Manchester, J. K., Semenkovich, C. F., and Gordon, J. I. (2007). Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc. Natl. Acad. Sci. U.S.A. 104, 979-984. doi: 10.1073/pnas.0605374104.
12. Bailey, M., Haverson, K., Inman, C., Harris, C., Jones, P., Corfield, G., et al. (2005). The development of the mucosal immune system pre-and post-weaning: balancing regulatory and effector function. Proc. Nutr. Soc. 64, 451-457. doi: 10.1079/PNS2005452.
13. Bassi, G. S., Brognara, F., Castania, J. A., Talbot, J., Cunha, T. M., Cunha, F. Q., et al. (2015). Baroreflex activation in conscious rats modulates the joint inflammatory response via sympathetic function. Brain Behav. Immun. 49, 140-147. doi: 10.1016/j.bbi.2015.05.002.
14. Becattini, B., Marone, R., Zani, F., Arsenijevic, D., Seydoux, J., Montani, J. P., et al. (2011). PI3Kγ within a nonhematopoietic cell type negatively regulates diet-induced thermogenesis and promotes obesity and insulin resistance. Proc. Natl. Acad. Sci. U.S.A. 108, E854-E863. doi: 10.1073/pnas.1106698108.
15. 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. doi: 10.1073/pnas.1001796107.
16. Belkaid, Y., and Hand, T. (2014). Role of the microbiota in immunity and inflammation. Cell. 157, 1-42. doi: 10.1016/j.cell.2014.03.011.
17. Bès-Houtmann, S., Roche, R., Hoareau, L., Gonthier, M. P., Festy, F., Caillens, H., et al. 2007. Presence of functional TLR2 TLR4 on human adipocytes. Histochem. Cell Biol. 127, 131-137. doi: 10.1007/s00418-006-0230-1.
18. Beutler, B. (2003). Innate immune responses to microbial poisons: discovery and function of the toll-Like receptors. Annu. Rev. Pharmacol. Toxicol. 43, 609-628. doi: 10.1146/annurev.pharmtox.43.100901.135729.
19. Bolus, W. R., Gutierrez, D. A., Kennedy, A. J., Anderson-Baucum, E. K., and Hasty, A. H. (2015). CCR2 deficiency leads to increased eosinophils, alternative macrophage activation, and type 2 cytokine expression in adipose tissue. J. Leukoc. Biol. 98, 1-11. doi: 10.1189/jlb.3HI0115-018R.
20. Brestoff, J. R., Kim, B. S., Saenz, S. A., Stine, R. R., Monticelli, L. A., Sonnenberg, G. F., et al. (2014). Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519, 242-246. doi: 10.1038/nature14115.
21. Burdette, A. M., and Hillb, T. D. (2008). An examination of processes linking perceived neighborhood disorder and obesity. Soc. Sci. Med. 67, 38-46. doi: 10.1016/j.socscimed.2008.03.029.
22. 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. doi: 10.1038/nm1166.
23. Cani, P. D., and Delzenne, N. M. (2009). The role of the gut microbiota in energy metabolism and metabolic disease. Curr. Pharm. Des. 15, 1546-1558. doi: 10.2174/138161209788168164.
24. Cani, P. D., Bibiloni, R., Knauf, C., Waget, A., Neyrinck, A. M., Delzenne, N. M., et al. (2008). Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57, 1470-1481. doi: 10.2337/db07-1403.
25. Cariou, B., van Harmelen, K., Duran-Sandoval, D., van Dijk, T. H., Grefhorst, A., Abdelkarim, M., et al. (2006). The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J. Biol. Chem. 281, 11039-11049. doi: 10.1074/jbc. M510258200.
26. Chiang, S. H., Bazuine, M., Lumeng, C. N., Geletka, L. M., Mowers, J., White, N. M., et al. 2009. The protein kinase IKKepsilon regulates energy balance in obese mice. Cell. 138, 961-975. doi: 10.1016/j.cell.2009.06.046.
27. Cho, K. W., Morris, D. L., DelProposto, J. L., Geletka, L., Zamarron, B., and Martinez-Santibanez, G. (2014). An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation. Cell Rep. 9, 605-617. doi: 10.1016/j.celrep.2014.09.004.
28. Cinti, S., Mitchell, G., Barbatelli, G., Murano, I., Ceresi, E., Faloia, E., et al. 2005. Adipocyte death defines macrophage localization function in adipose tissue of obese mice humans. J Lipid Res. 46, 2347-2355. doi: 10.1194/jlr. M500294-JLR200.
29. Clarke, S. F., Murphy, E. F., Nilaweera, K., Ross, P. R., Shanahan, F., O'Toole, P. W., et al. (2012). The gut microbiota and its relationship to diet and obesity. Gut Microbes. 3, 186-202. doi: 10.4161/gmic.20168.
30. Cotillard, A., Kennedy, S. P., Kong, L. C., Prifti, E., Pons, N., Chatelier, E. L., et al. (2013). Dietary intervention impact on gut microbial gene richness. Nature 500, 585-588. doi: 10.1038/nature12480.
31. Dalmas, E., Clément, K., and Guerre-Millo, M. (2011). Defining macrophage phenotype and function in adipose tissue. Trends Immunol. 32, 307-314. doi: 10.1016/j.it.2011.04.008.
32. Dasu, M. R., and Jialal, I. (2010). Free fatty acids in the presence of high glucose amplify monocyte inflammation via toll-like receptors. Am. J. Physiol. Endocrinol. Metab. 300, E145-E154. doi: 10.1152/ajpendo.00490.2010.
33. David, L. A., Maurice, C. F., Carmody, R. N., Gootenberg, D. B., Button, J. E., Wolfe, B. E., et al. (2014). Diet rapidly and reproducibly alters the human gut microbiome. Nature 505, 559-563. doi: 10.1038/nature12820.
34. Davis, J. E., Braucher, D. R., Walker-Daniels, J., and Spurlock, M. E. (2011). Absence of Tlr2 protects against high-fat diet-induced inflammation and results in greater insulin-stimulated glucose transport in cultured adipocytes. J. Nutr. Biochem. 22, 136-141. doi: 10.1016/j.jnutbio.2009.12.008.
35. 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. doi: 10.1038/oby.2008.210.
36. de Mello, V. D., Kolehmainen, M., Pulkkinen, L., Schwab, U., Mager, U., Laaksonen, D. E., et al. (2008). Downregulation of genes involved in NFkappaB activation in peripheral blood mononuclear cells after weight loss is associated with the improvement of insulin sensitivity in individuals with the metabolic syndrome: the GENOBIN study. Diabetologia 51, 2060-2067. doi: 10.1007/s00125-008-1132-7.
37. de Theije, C. G., Wopereis, H., Ramadan, M., van Eijndthoven, T., Lambert, J., Knol, J., et al. (2014). Altered gut microbiota and activity in a murine model of autism spectrum disorders. Brain Behav. Immun. 37, 197-206. doi: 10.1016/j.bbi.2013.12.005.
38. de Vasconcelos, D. I. B., Leite, J. A., Carneiro, L. T., Piuvezam, M. R., Lima, M. R. V., de Morais, L. C. L., et al. (2011). Anti-inflammatory and antinociceptive activity of ouabain in mice. Mediators Inflamm. 2011, 1-11. doi: 10.1155/2011/912925.
39. Deban, L., Bottazzi, B., Garlanda, C., de la Torre, Y. M., and Mantovani, A. (2009). Pentraxins: multifunctional proteins at the interface of innate immunity and inflammation. Biofactors 35, 138-145. doi: 10.1002/biof.21.
40. DeMarco, V. G., Aroor, A. R., and Sowers, J. R. (2014). The pathophysiology of hypertension in patients with obesity. Nat. Rev. Endocrinol. 10, 364-376. doi: 10.1038/nrendo.2014.44.
41. Du Clos, T. W. (2013). Pentraxins: structure, function, and role in inflammation. ISRN Inflamm. 2013, 1-22. doi: 10.1155/2013/379040.
42. Elgazar-Carmon, V., Rudich, A., Hadad, N., and Levy, R. (2008). Neutrophils transiently infiltrate intra-abdominal fat early in the course of high-fat feeding. J. Lipid Res. 49, 1894-1903. doi: 10.1194/jlr. M800132-JLR200.
43. Elinav, E., Strowig, T., Kau, A. L., Henao-Mejia, J., Thaiss, C. A., Booth, C. J., et al. (2011). NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145, 745-757. doi: 10.1016/j.cell.2011.04.022.
44. Emanuela, F, Grazia, M., Marco de R., Maria Paola, L., Giorgio, F., and Marco, B. (2012). Inflammation as a link between obesity and metabolic syndrome. J. Nutr. Metab. 2012, 1-7. doi: 10.1155/2012/476380.
45. Ferrante, A. W. Jr. (2013). The immune cells in adipose tissue. Diabetes Obes. Metab. 3, 34-38. doi: 10.1111/dom.12154.
46. Fresno, M., Alvarez, R., and Cuesta, N. (2011). Toll-like receptors, inflammation, metabolism and obesity. Arch. Physiol. Biochem. 117, 151-164. doi: 10.3109/13813455.2011.562514.
47. Fujimura, E. K., Slusher, N. A., Cabana, M. D., and Lynch, S. V. (2010). Role of the gut microbiota in defining human health. Expert Rev. Anti Infect. Ther. 8, 435-454. doi: 10.1586/eri.10.14.
48. Gregor, M. F., and Hotamisligil, G. S. (2011). Inflammatory mechanisms in obesity. Annu. Rev. Immunol. 29, 415-445. doi: 10.1146/annurev-immunol-031210-101322.
49. Guinane, C. M., and Cotter, P. D. (2013). Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Ther. Adv. Gastroenterol. 6, 295-308. doi: 10.1177/1756283X13482996.
50. Han, M. S., Jung, D. Y., Morel, C., Lakhani, S. A., Kim, J. K., Flavell, R. A., et al. (2013). JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation. Science 339, 218-222. doi: 10.1126/science.1227568.
51. Hawkins, P. T., and Stephens, L. R. (2015). PI3K signalling in inflammation. Biochim. Biophys. Acta 1851, 882-897. doi: 10.1016/j.bbalip.2014.12.006.
52. Hayashi, F., Smith, K. D., Ozinsky, A., Hawn, T. R., Eugene, C. Y., Goodlett, D. R., et al. (2001). The innate immune response to bacterial flagellin is mediated bytoll-like receptor 5. Nature 410, 1099-1103. doi: 10.1038/35074106.
53. Hemmi, H., Takeuchi, O., Kawai, T., Kaisho, T., Sato, S., Sanjo, H., et al. (2000). A toll-like receptor recognizes bacterial DNA. Nature 408, 740-745. doi: 10.1038/35047123.
54. Himes, R. W., and Smith, C. W. (2010). Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J. 24, 731-739. doi: 10.1096/fj.09-141929.
55. Hirosumi, J., Tuncman, G., Chang, L., Görgün, C. Z., Uysal, K. T., Maeda, K., et al. (2002). A central role for JNK in obesity and insulin resistance. Nature 420, 333-336. doi: 10.1038/nature01137.
56. Hirota, S. A., Ng, J., Lueng, A., Khajah, M., Parhar, K., Li, Y., et al. (2011). NLRP3 inflammasome plays a key role in the regulation of intestinal homeostasis. Inflamm. Bowel Dis. 17, 1359-1372. doi: 10.1002/ibd.21478.
57. Hofmann, A. F., and Eckmann, L. (2006). How bile acids confer gut mucosal protection against bacteria. Proc. Natl. Acad. Sci. U.S.A. 103, 4333-4334. doi: 10.1073/pnas.0600780103.
58. Hooper, L. V., Wong, M. H., Thelin, A., Hansson, L., Falk, P. G., and Gordon, J. I. 2001. Molecular analysis of commensal host-microbial relationships in the intestine. Science 291, 881-884. doi: 10.1126/science.291.5505.881.
59. Hooper, V. L., Midtvedt, T., and Gordon, J. I. (2002). How host-microbial interactions shape the nutrient environment of the mammalian intestine. Annu. Rev. Nutr. 22, 283-307. doi: 10.1146/annurev.nutr.22.011602.092259.
60. Hornef, M. W., and Bogdan, C. (2005). The role of epithelial toll-like receptor expression in host defense and microbial tolerance. J Endotoxin Res. 11, 124-128. doi: 10.1179/096805105X35224.
61. Hornung, V., Biller, G. M., Bourquin, C., Ablasser, A., Schlee, M., Uematsu, S., et al. (2005). Sequence-specific potent induction of IFN-a by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nat. Med. 11, 263-270. doi: 10.1038/nm1191.
62. Hwa, C. H., Bae, Y. C., and Jung, J. S. (2006). Role of toll-like receptors on human adipose-derived stromal cells. Stem Cells 24, 2744-2752. doi: 10.1634/stemcells.2006-0189.
63. Inagaki, T., Moschetta, A., Lee, Y. K., Peng, L., Zhao, G., Downes, M., et al. (2006). Regulation of antibacterial defense in the small intestine by the nuclear bile acid receptor. Proc. Natl. Acad. Sci. U.S.A. 103, 3920-3925. doi: 10.1073/pnas.0509592103.
64. Inouye, K. E., Shi, H., Howard, J. K., Daly, C. H., Lord, G. M., Rollins, B. J., et al. (2007). Absence of CC chemokine ligand 2 does not limit obesity-associated infiltration of macrophages into adipose tissue. Diabetes 56, 2242-2250. doi: 10.2337/db07-0425.
65. Janeway, C. A., and Medzhitov, R. (2002). Innate immune recognition. Annu. Rev. Immunol. 20, 197-216. doi: 10.1146/annurev.immunol.20.083001.084359.
66. Jauch-Chara, K., and Oltmanns, K. M. (2014). Obesity-a neuropsychological disease? Systematic review and neuropsychological model. Prog. Neurobiol. 114, 84-101. doi: 10.1016/j.pneurobio.2013.12.001.
67. Jia, L., Vianna, C. R., Fukuda, M., Berglund, E. D., Liu, C., Tao, C., et al. (2014). Hepatocyte Toll-like receptor 4 regulates obesity-induced inflammation and insulin resistance. Nat Commun. 5, 1-11. doi: 10.1038/ncomms4878.
68. Kadook, Y., Sato, M., Imaizumi, K., Ogawa, A., Ikuyama, K., Akai, Y., et al. (2010). Regulation of abdominal adiposity by probiotics (Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial. Eur. J. Clin. Nutr. 64, 636-643. doi: 10.1038/ejcn.2010.19.
69. Kanczkowski, W., Ziegler, C. G., Zacharowski, K., and Bornstein, S. R. (2008). Toll-like receptors in endocrine disease and diabetes. Neuroimmunomodulation 15, 54-60. doi: 10.1159/000135624.
70. Kanda, H., Tateya, S., Tamori, Y., Kotani, K., Hiasa, K., Kitazawa, R., et al. (2006). MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494-1505. doi: 10.1172/JCI26498.
71. Kawai, T., and Akira, S. (2010). The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat. Immunol. 11, 373-384. doi: 10.1038/ni.1863.
72. Kawasaki, T., and Kawai, T. (2014). Toll-Like receptor signaling pathways. Front. Immunol. 5:461. doi: 10.3389/fimmu.2014.00461.
73. Kelly, D., Campbell, J. I., King, T. P., Grant, G., Jansson, E. A., Coutts, A. G. P., et al. (2004). Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-γ and RelA. Nat. Immunol. 5, 104-112. doi: 10.1038/ni1018.
74. Keophiphath, M., Rouault, C., Divoux, A., Clément, K., and Lacasa, D. (2010). CCL5 promotes macrophage recruitment and survival in human adipose tissue. Arterioscler. Thromb. Vasc. Biol. 30, 39-45. doi: 10.1161/ATVBAHA.109.197442.
75. Khan, S. A., Ali, A., Khan, S. A., Zahran, S. A., Damanhouri, G., Azhar, E., et al. (2014). Unraveling the complex relationship triad between lipids, obesity, and inflammation. Mediators Inflamm. 2014, 1-16. doi: 10.1155/2014/502749.
76. Kim, D., Kim, J., Yoon, J. H., Ghim, J., Yea, K., Song, P., et al. (2014). CXCL12 secreted from adipose tissue recruits macrophages and induces insulin resistance in mice. Diabetologia 57, 1456-1465. doi: 10.1007/s00125-014-3237-5.
77. Kim, K. A., Gu, W., Lee, I. A., Joh, E. H., and Kim, D. H. (2012). High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS ONE 7:e47713. doi: 10.1371/journal.pone.0047713.
78. Kim, K. Y., Jeong, H. J., and Kim, H. M. (2013). The role of T-bet in obesity: lack of T-bet causes obesity in male mice. J. Nutr. Biochem. 24, 240-247. doi: 10.1016/j.jnutbio.2012.05.010.
79. Kirk, E. A., Sagawa, Z. K., McDonald, T. O., O'Brien, K. D., and Heinecke, J. W. (2008). Monocyte chemoattractant protein deficiency fails to restrain macrophage infiltration into adipose tissue. Diabetes 57, 1254-1261. doi: 10.2337/db07-1061.
80. Kitade, H., Sawamoto, K., Nagashimada, M., Inoue, H., Yamamoto, Y., Sai, Y., et al. (2012). CCR5 plays a critical role in obesity-induced adipose tissue inflammation and insulin resistance by regulating both macrophage recruitment and M1/M2 status. Diabetes 61, 1680-1690. doi: 10.2337/db11-1506.
81. Kobayashi, N., Ueki, K., Okazaki, Y., Iwane, A., Kubota, N., Ohsugi, M., et al. (2011). Blockade of class IB phosphoinositide-3 kinase ameliorates obesity-induced inflammation and insulin resistance. Proc. Natl. Acad. Sci. U.S.A. 108, 5753-5758. doi: 10.1073/pnas.1016430108.
82. Kraakman, M. J., Kammoun, H. L., Allen, T. L., Deswaerte, V., Henstridge, D. C., Estevez, E., et al. (2015). Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metab. 21, 403-416. doi: 10.1016/j.cmet.2015.02.006.
83. Kraakman, M. J., Murphy, A. J., Jandeleit-Dahm, K., and Kammoun, H. L. (2014). Macrophage polarization in obesity and type 2 diabetes: weighing down our understanding of macrophage function? Front. Immunol. 5:470. doi: 10.3389/fimmu.2014.00470.
84. Krinninger, P., Ensenauer, R., Ehlers, K., Rauh, K., Stoll, J., Krauss-Etschmann, S., et al. (2014). Peripheral monocytes of obese women display increased chemokine receptor expression and migration capacity. J. Clin. Endocrinol. Metab. 99, 2500-2509. doi: 10.1210/jc.2013-2611.
85. Latz, E., Xiao, T. S., and Stutz, A. (2013). Activation and regulation of the inflammasomes. Nat. Rev. Immunol. 13, 397-411. doi: 10.1038/nri3452.
86. Lee, C. C., Avalos, A. M., and Ploegh, H. L. (2012). Accessory molecules for toll-like receptors and their function. Nat. Rev. Immunol. 12, 168-179. doi: 10.1038/nri3151.
87. Lee, J. Y., Sohn, K. H., Rhee, S. H., and 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, 16683-16689. doi: 10.1074/jbc. M011695200.
88. Lee, J. Y., Ye, J., Gao, Z., Youn, H. S., Lee, W. H., Zhao, L., et al. (2003). Reciprocal modulation of toll-like receptor-4 signaling pathways involving MyD88 and phosphatidylinositol 3-kinase/AKT by saturated and polyunsaturated fatty acids. J. Biol. Chem. 278, 37041-37051. doi: 10.1074/jbc. M305213200.
89. Leite, J. A., Alves, A. K. A., Galvão, J. G. M., Teixeira, M. P., Cavalcante-Silva, L. H. A., Scavone, C., et al. (2015). Ouabain modulates zymosan-induced peritonitis in mice. Mediators Inflamm. 2015, 1-12. doi: 10.1155/2015/265798.
90. Lemaitre, B., Nicolas, E., Michaut, L., Reichhart, J. M., and Hoffmann, J. A. (1996). The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973-983. doi: 10.1016/S0092-8674(00)80172-5.
91. Ley, R. E., Bäckhed, F., Turnbaugh, P., Lozupone, C. A., Knight, R. D., and Gordon, J. I. (2005). Obesity alters gut microbial ecology. Proc. Natl. Acad. Sci. U.S.A. 102, 11070-11075. doi: 10.1073/pnas.0504978102.
92. Liu, K., Zhao, E., Ilyas, G., Lalazar, G., Lin, Y., Haseeb, M., et al. (2015). Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization. Autophagy 11, 271-284. doi: 10.1080/15548627.2015.1009787.
93. Lotz, M., Gütle, D., Walther, S., Ménard, S., Bogdan, C., and Hornef, M. W. (2003). Postnatal acquisition of endotoxin tolerance in intestinal epithelial cells. J. Exp. Med. 203, 973-984. doi: 10.1084/jem.20050625.
94. + T cells: differentiation and functions. Clin. Dev. Immunol. 2012, 1-12. doi: 10.1155/2012/925135.
95. Luo, L., Wall, A. A., Yeo, J. C., Condon, N. D., Norwood, S. J., Schoenwaelder, S., et al. (2014). Rab8a interacts directly with PI3Kγ to modulate TLR4-driven PI3K and mTOR signalling. Nat. Commun. 15, 1-13. doi: 10.1038/ncomms5407.
96. Lynch, L., Michelet, X., Zhang, S., Brennan, P. J., Moseman, A., Lester, C., et al. (2015). Regulatory iNKT cells lack expression of the transcription factor PLZF and control the homeostasis of T(reg) cells and macrophages in adipose tissue. Nat. Immunol. 16, 85-95. doi: 10.1038/ni.3047.
97. Ma, K., Saha, P. K., Chan, L., and Moore, D. D. (2006). Farnesoid X receptor is essential for normal glucose homeostasis. J. Clin. Invest. 116, 1102-1109. doi: 10.1172/JCI25604.
98. Ma, Y., Gao, M., Sun, H., and Liu, D. (2015). Interleukin-6 gene transfer reverses body weight gain and fatty liver in obese mice. Biochim. Biophys. Acta 1852, 1001-1011. doi: 10.1016/j.bbadis.2015.01.017.
99. Martelli, D., McKinley, M. J., and McAllen, R. M. (2014). The cholinergic anti-inflammatory pathway: a critical review. Auton. Neurosci. 182, 65-69. doi: 10.1016/j.autneu.2013.12.007.
100. Martin, R., Nauta, A. J., Amor, K. B., Knippels, L. M. J., Knol, J., and Garssen, J. (2010). Early life: gut microbiota and immune development in infancy. Benef. Microbes 1, 367-382. doi: 10.3920/BM2010.0027.
101. Mauer, J., Chaurasia, B., Goldau, J., Vogt, M. C., Ruud, J., Nguyen, K. D., et al. (2014). Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity associated resistance to insulin. Nat. Immunol. 15, 423-430. doi: 10.1038/ni.2865.
102. McGill, A. (2014). Causes of metabolic syndrome and obesity-related co-morbidities part 1: a composite unifying theory review of human-specific co-adaptations to brain energy consumption. Arch. Public Health 72, 1-13. doi: 10.1186/2049-3258-72-30.
103. McLaughlin, T., Liu, L. F., Lamendola, C., Shen, L., Morton, J., Rivas, H., et al. (2014). T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler. Thromb. Vasc. Biol. 34, 2637-2643. doi: 10.1161/ATVBAHA.114.304636.
104. Medzhitov, R. (2008). Origin and physiological roles of inflammation. Nature 454, 428-435. doi: 10.1038/nature07201.
105. Medzhitov, R. (2010). Inflammation 2010: new adventures of an old flame. Cell 140, 771-776. doi: 10.1016/j.cell.2010.03.006.
106. Medzhitov, R., Preston-Hurlburt, P., and Janeway, C. A. Jr. (1997). A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394-397.
107. Medzhitov, R. (2007). Recognition of microorganisms and activation of the immune response. Nature 449, 819-826. doi: 10.1038/nature06246.
108. Merritt, M. E., and Donaldson, J. R. (2009). Effect of bile salts on the DNA and membrane integrity of enteric bacteria. J. Med. Microbiol. 58, 1533-1541. doi: 10.1099/jmm.0.014092-0.
109. Milanski, M., Degasperi, G., Coope, A., Morari, J., Denis, R., Cintra, D. E., et al. (2009). Saturated fatty acids produce an inflammatory response predominantly through the activation of TLR4 signaling in hypothalamus: implications for the pathogenesis of obesity. J. Neurosci. 29, 359-370. doi: 10.1523/JNEUROSCI.2760-08.2009.
110. Mirhafez, S. R., Mohebati, M., Disfani, M. F., Karimian, M. S., Ebrahimi, M., Avan, A., et al. (2014). An imbalance in serum concentrations of inflammatory and anti-inflammatory cytokines in hypertension. J. Am. Soc. Hypertens. 8, 614-623. doi: 10.1016/j.jash.2014.05.007.
111. Mitchell, S., and Shaw, D. (2015). The worldwide epidemic of female obesity. Best Pract. Res. Clin. Obstet. Gynaecol. 29, 289-299. doi: 10.1016/j.bpobgyn.2014.10.002.
112. Miyoshi, M., Ogawa, A., Higurashi, S., and Kadooka, Y. (2014). Anti-obesity effect of Lactobacillus gasseri SBT2055 accompanied by inhibition of pro-inflammatory gene expression in the visceral adipose tissue in diet-induced obese mice. Eur. J. Nutr. 53, 599-606. doi: 10.1007/s00394-013-0568-9.
113. Nara, N., Nakayama, Y., Okamoto, S., Tamura, H., Kiyono, M., Muraoka, M., et al. (2007). Disruption of CXC motif chemokine ligand-14 in mice ameliorates obesity-induced insulin resistance. J. Biol. Chem. 282, 30794-30803. doi: 10.1074/jbc. M700412200.
114. Nguyen, M. T., Satoh, H., Favelyukis, S., Babendure, J. L., Imamura, T., Sbodio, J. I., et al. (2005). JNK and tumor necrosis factor-alpha mediate free fatty acid-induced insulin resistance in 3T3-L1 adipocytes. J. Biol. Chem. 280, 35361-35371. doi: 10.1074/jbc. M504611200.
115. Nordlander, S., Pott, J., and Maloy, K. J. (2014). NLRC4 expression in intestinal epithelial cells mediates protection against an enteric pathogen. Mucosal Immunol. 7, 775-785. doi: 10.1038/mi.2013.95.
116. Olefsky, J. M. (2009). IKKepsilon: a bridge between obesity and inflammation. Cell 138, 834-836. doi: 10.1016/j.cell.2009.08.018.
117. Orr, J. S., Puglisi, M. J., Ellacott, K. L., Lumeng, C. N., Wasserman, D. H., and Hasty, A. H. (2012). Toll-like receptor 4 deficiency promotes the alternative activation of adipose tissue macrophages. Diabetes 61, 2718-2727. doi: 10.2337/db11-1595.
118. Park, D. Y., Ahn, Y. T., Park, S. H., Huh, C. S., Yoo, S. R., Yu, R., et al. (2013). Supplementation of Lactobacillus curvatus HY7601 and Lactobacillus plantarum KY1032 in diet-induced obese mice is associated with gut microbial changes and reduction in obesity. PLoS ONE 8:e59470. doi: 10.1371/journal.pone.0059470.
119. Pekkala, S., Munukka, E., Kong, L., Pöllänen, E., Autio, R., Roos, C., et al. (2015). Toll-like receptor 5 in obesity: the role of gut microbiota and adipose tissue inflammation. Obesity 23, 581-590. doi: 10.1002/oby.20993.
120. Perino, A., Beretta, M., Kiliæ, A., Ghigo, A., Carnevale, D., Repetto, I. E., et al. (2014). Combined inhibition of PI3Kß and PI3Kγ reduces fat mass by enhancing a-MSH-dependent sympathetic drive. Sci. Signal. 18, 1-12. doi: 10.1126/scisignal.2005485.
121. Perry, R. J., Camporez, J. P., Kursawe, R., Titchenell, P. M., Zhang, D., Perry, C. J., et al. (2015). Hepatic acetyl CoA links adipose tissue inflammation to hepatic insulin resistance and type 2 diabetes. Cell 160, 745-758. doi: 10.1016/j.cell.2015.01.012.
122. Pietsch, J., Batra, A., Stroh, T., Fedke, I., Glauben, R., Okur, B., et al. (2006). Toll-like receptor expression and response to specific stimulation in adipocytes and preadipocytes: on the role of fat in inflammation. Ann. N.Y. Acad. Sci. 1072, 407-409. doi: 10.1196/annals.1326.021.
123. dimCD16+ and CD14+CD16+ monocytes in obesity and during weight loss: relationships with fat mass and subclinical atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 31, 2322-2330. doi: 10.1161/ATVBAHA.111.230979.
124. Poltorak, A., He, X., Smirnova, I., Liu, M. Y., Van Huffel, C., Du, X., et al. (1998a). Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science 282, 2085-2088. doi: 10.1126/science.282.5396.2085.
125. Poltorak, A., Smirnova, I., He, X., Liu, M. Y., Van Huffel, C., Birdwell, D., et al. (1998b). Genetic and physical mapping of the LpsLocus: identification of the Toll-4 receptor as a candidate gene in the critical region. Blood Cells Mol. Dis. 24, 340-355. doi: 10.1006/bcmd.1998.0201.
126. Pott, J., and Hornef, M. (2012). Innate immune signalling at the intestinal epithelium in homeostasis and disease. EMBO Rep. 13, 684-698. doi: 10.1038/embor.2012.96.
127. Poulain-Godefroy, O., and Froguel, P. (2007). Preadipocyte response and impairment of differentiation in an inflammatory environment. Biochem. Biophys. Res. Commun. 356, 662-667. doi: 10.1016/j.bbrc.2007.03.053.
128. Prawitt, J., Abdelkarim, M., Stroeve, J. H., Popescu, I., Duez, H., Velagapudi, V. R., et al. (2011). Farnesoid X receptor deficiency improves glucose homeostasis in mouse models of obesity. Diabetes 60, 1861-1871. doi: 10.2337/db11-0030.
129. Rabot, S., Membrez, M., Bruneau, A., Gérard, P., Harach, T., Moser, M., et al. (2010). Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism. FASEB J. 24, 4948-4959. doi: 10.1096/fj.10-164921.
130. Raoult, D. (2009). Probiotics and obesity: a link? Nat. Rev. Microbiol. 7, 616. doi: 10.1038/nrmicro2209.
131. Ren, D. L., Sun, A. A., Li, Y. J., Chen, M., Ge, S. C., and Hu, B. (2015). Exogenous melatonin inhibits neutrophil migration through suppression of ERK activation. J. Endocrinol. 227, 49-60. doi: 10.1530/JOE-15-0329.
132. Reyna, S. M., Ghosh, S., Tantiwong, P., Meka, C. S., Eagan, P., Jenkinson, C. P., et al. (2008). Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes 57, 2595-2602. doi: 10.2337/db08-0038.
133. Ridlon, J. M., Kang, D. J., and Hylemon, P. B. (2006). Bile salt biotransformations by human intestinal bacteria. J. Lipid Res. 47, 241-259. doi: 10.1194/jlr. R500013-JLR200.
134. Ridlon, J. M., Kang, D. J., Hylemon, P. B., and Bajaj, J. S. (2014). Bile acids and the gut microbiome. Curr. Opin. Gastroenterol. 30, 332-338. doi: 10.1097/MOG.0000000000000057.
135. Rocha, V. Z., Folco, E. J., Sukhova, G., Shimizu, K., Gotsman, I., Vernon, A. H., et al. (2008). Interferon-gamma, a Th1 cytokine, regulates fat inflammation: a role for adaptive immunity in obesity. Circ. Res. 103, 467-476. doi: 10.1161/CIRCRESAHA.108.177105.
136. Rumore, M. M., and Kim, K. S. (2010). Potential role of salicylates in type 2 diabetes. Ann. Pharmacother. 44, 1207-1221. doi: 10.1345/aph.1M483.
137. Sabio, G., Cavanagh-Kyros, J., Barrett, T., Jung, D. Y., Ko, H. J., Ong, H., et al. 2010. Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1. Genes Dev. 24, 256-264. doi: 10.1101/gad.1878510.
138. Sanz, Y., and Moya-Pérez, A. (2014). Microbiota, inflammation and obesity. Adv. Exp. Med. Biol. 817, 291-317. doi: 10.1007/978-1-4939-0897-4_14.
139. Sárvári, A. K., Doan-Xuan, Q. M., Bacsó, Z., Csomós, I., Balajthy, Z., and Fésüs, L. (2015). Interaction of differentiated human adipocytes with macrophages leads to trogocytosis and selective IL-6 secretion. Cell Death Dis. 22, 1-9. doi: 10.1038/cddis.2014.579.
140. Schloss, P. D., and Handelsman, J. (2004). Status of the microbial census. Microbiol. Mol. Biol. Rev. 68, 686-691. doi: 10.1128/MMBR.68.4.686-691.2004.
141. Schmid, M. C., Avraamides, C. J., Dippold, H. C., Franco, I., Foubert, P., Ellies, L. G., et al. (2011). Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 19, 715-727. doi: 10.1016/j.ccr.2011.04.016.
142. Sekirov, I., Russell, S. L., Antunes, L. C., and Finlay, B. B. (2010). Gut microbiota in health and disease. Physiol. Rev. 90, 859-904. doi: 10.1152/physrev.00045.2009.
143. Sell, H., Habich, C., and Eckel, J. (2012). Adaptive immunity in obesity and insulin resistance. Nat. Rev. Endocrinol. 8, 709-716. doi: 10.1038/nrendo.2012.
144. Sellin, M. E., Maslowski, K. M., Maloy, K. J., and Hardt, W. D. (2015). Inflammasomes of the intestinal epithelium. Trends Immunol. 36, 442-450. doi: 10.1016/j.it.2015.06.002.
145. Sellin, M. E., Müller, A. A., Felmy, B., Dolowschiak, T., Diard, M., Tardivel, A., et al. (2014). Epithelium-intrinsic NAIP/NLRC4 inflammasome drives infected enterocyte expulsion to restrict Salmonella replication in the intestinal mucosa. Cell Host Microbe 16, 237-248. doi: 10.1016/j.chom.2014.07.001.
146. Shaharyar, S., Roberson, L. L., Jamal, O., Younus, A., Blaha, M. J., Ali, S. S., et al. (2015). Obesity and metabolic phenotypes (metabolically healthy and unhealthy variants) are significantly associated with prevalence of elevated C-reactive protein and hepatic steatosis in a large healthy Brazilian population. J. Obes. 2015, 1-6. doi: 10.1155/2015/178526.
147. Shi, H., Kokoeva, M. V., Inouye, K., Tzameli, I., Yin, H., and Flier, J. S. (2006). TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Invest. 116, 3015-3025. doi: 10.1172/JCI28898.
148. Shibolet, O., and Podolsky, D. K. (2007). TLRs in the Gut. IV. Negative regulation of toll-like receptors and intestinal homeostasis: addition by subtraction. Am. J. Physiol. Gastrointest. Liver Physiol. 292, G1469-G1473. doi: 10.1152/ajpgi.00531.2006.
149. Shin, J. H., Shin, D. W., and Noh, M. (2009). Interleukin-17A inhibits adipocyte differentiation in human mesenchymal stem cells and regulates pro-inflammatory responses in adipocytes. Biochem. Pharmacol. 77, 1835-1844. doi: 10.1016/j.bcp.2009.03.008.
150. 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. doi: 10.1016/j.cmet.2007.09.011.
151. Štofilová, J., Szabadosová, V., Hrèková, G., Salaj, R., Bertková, I., and Hijová, E. (2015). Co-administration of a probiotic strain Lactobacillus plantarum LS/07 CCM7766 with prebiotic inulin alleviates the intestinal inflammation in rats exposed to N, N-dimethylhydrazine. Int. Immunopharmacol. 24, 361-368. doi: 10.1016/j.intimp.2014.12.022.
152. Strissel, K. J., DeFuria, J., Shaul, M. E., Bennett, G., Greenberg, A. S., and Obin, M. S. (2010). T-cell recruitment and Th1 polarization in adipose tissue during diet-induced obesity in C57BL/6 mice. Obesity (Silver. Spring). 18, 1918-1925. doi: 10.1038/oby.2010.1.
153. Subramanian, V., and Ferrante, A. W. Jr. (2009). Obesity, inflammation, and macrophages. Nestle Nutr. Workshop Ser. Pediatr. Program. 63, 151-159. doi: 10.1159/000209979.
154. Suganami, T., Mieda, T., Itoh, M., Shimoda, Y., Kamei, Y., and Ogawa, Y. (2007). 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. doi: 10.1016/j.bbrc.2006.12.190.
155. Takeda, S., Sato, N., and Morishita, R. (2014). Systemic inflammation, blood-brain barrier vulnerability and cognitive/non-cognitive symptoms in Alzheimer disease: relevance to pathogenesis and therapy. Front. Aging Neurosci. 6:171. doi: 10.3389/fnagi.2014.00171.
156. Takeuchi, O., Hoshino, K., Kawai, T., Sanjo, H., Takada, H., Ogawa, T., et al. (1999). Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity 11, 443-451. doi: 10.1016/S1074-7613(00)80119.
157. Talukdar, S., Oh da, Y., Bandyopadhyay, G., Li, D., Xu, J., McNelis, J., et al. (2012). Neutrophils mediate insulin resistance in mice fed a high-fat diet through secreted elastase. Nat. Med. 18, 1407-1412. doi: 10.1038/nm.2885.
158. Thomas, C., Gioiello, A., Noriega, L., Strehle, A., Oury, J., Rizzo, G., et al. (2009). TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 10, 167-177. doi: 10.1016/j.cmet.2009.08.001.
159. Trayhurn, P. (2005). The biology of obesity. Proc. Nutr. Soc. 64, 31-38. doi: 10.1079/PNS2004406.
160. Tremaroli, V., and Bäckhed, F. (2012). Functional interactions between the gut microbiota and host metabolism. Nature 489, 242-249. doi: 10.1038/nature11552.
161. Tsukumo, D. M., Carvalho-Filho, M. A., Carvalheira, J. B., Prada, P. O., Hirabara, S. M., Schenka, A. A., et al. (2007). Loss-of-function mutation in toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56, 1986-1998. doi: 10.2337/db06-1595.
162. Turnbaugh, P. J., Bäckhed, F., Fulton, L., and Gordon, J. I. (2008). Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome. Cell Host Microbe 3, 213-223. doi: 10.1016/j.chom.2008.02.015.
163. Turnbaugh, P. J., Hamady, M., Yatsunenko, T., Cantarel, B. L., Duncan, A., Ley, R. E., et al. (2009). A core gut microbiome in obese and lean twins. Nature 457, 480-484. doi: 10.1038/nature07540.
164. Turnbaugh, P. J., Ley, R. E., Mahowald, M. A., Magrini, V., Mardis, E. R., and Gordon, J. I. (2006). An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444, 1027-1031. doi: 10.1038/nature05414.
165. Ukibe, K., Miyoshi, M., and Kadooka, Y. (2015). Administration of Lactobacillus gasseri SBT2055 suppresses macrophage infiltration into adipose tissue in diet-induced obese mice. Br. J. Nutr. 114, 1180-1187. doi: 10.1017/S0007114515002627.
166. Vael, C., and Desager, K. (2009). The importance of the development of the intestinal microbiota in infancy. Curr. Opin. Pediatr. 21, 794-800. doi: 10.1097/MOP.0b013e328332351b.
167. Vilahur, G., López-Bernal, S., Camino, S., Mendieta, G., Padró, T., and Badimon, L. (2015). Lactobacillus plantarum CECT 7315/7316 intake modulates the acute and chronic innate inflammatory response. Eur. J. Nutr. 54, 1161-1171. doi: 10.1007/s00394-014-0794-9.
168. Vitseva, O. I., Tanriverdi, K., Tchkonia, T. T., Kirkland, J. L., McDonnell, M. E., Apovian, C. M., et al. (2008). Inducible toll-like receptor and NF-kappaB regulatory pathway expression in human adipose tissue. Obesity 16, 932-937. doi: 10.1038/oby.2008.25.
169. Walsh, C. J., Guinane, C. M., O'Toole, P. W., and Cotter, P. D. (2014). Beneficial modulation of the gut microbiota. FEBS Lett. 588, 4120-4130. doi: 10.1016/j.febslet.2014.03.035.
170. Weichhart, T., Costantino, G., Poglitsch, M., Rosner, M., Zeyda, M., Stuhlmeier, K. M., et al. (2008). The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 29, 565-577. doi: 10.1016/j.immuni.2008.08.012.
171. Weisberg, S. P., Hunter, D., Huber, R., Lemieux, J., Slaymaker, S., Vaddi, K., et al. (2006). CCR2 modulates inflammatory and metabolic effects of high-fat feeding. J. Clin. Invest. 116, 115-124. doi: 10.1172/JCI24335.
172. Wells, J. M., Rossi, O., Meijerink, M., and van Baarlen, P. (2011). Epithelial crosstalk at the microbiota-mucosal interface. Proc. Natl. Acad. Sci. U.S.A. 108, 4607-4614. doi: 10.1073/pnas.1000092107.
173. Wensveen, F. M., Jelenčić, V., Valentić, S., Šestan, M., Wensveen, T. T., Theurich, S., et al. (2015). NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat. Immunol. 16, 376-385. doi: 10.1038/ni.3120.
174. Werling, D., and Jungi, W. T. (2003). Toll-like receptors linking innate and adaptative immune response. Vet. Immunol. Immunopathol. 91, 1-12. doi: 10.1016/S0165-2427(02)00228-3.
175. Williams, M. J., Rodriguez, A., Kimbrell, D. A., and Eldon, E. D. (1997). The 18-wheeler mutation reveals complex antibacterial gene regulation in Drosophila host defense. EMBO J. 16, 6120-6130. doi: 10.1093/emboj/16.20.6120.
176. Willing, B. P., Gill, N., and Finlay, B. B. (2010). The role of the immune system in regulating the microbiota. Gut Microbes. 1, 213-223. doi: 10.4161/gmic.1.4.12520.
177. Winer, S., Paltser, G., Chan, Y., Tsui, H., Engleman, E., Winer, D., et al. (2009). Obesity predisposes to Th17 bias. Eur. J. Immunol. 39, 2629-2635. doi: 10.1002/eji.200838893.
178. Wlodarska, M., Thaiss, C. A., Nowarski, R., Henao-Mejia, J., Zhang, J. P., Brown, E. M., et al. (2014). NLRP6 inflammasome orchestrates the colonic host-microbial interface by regulating goblet cell mucus secretion. Cell 156, 1045-1059. doi: 10.1016/j.cell.2014.01.026.
179. Wymann, M. P., and Solinas, G. (2013). Inhibition of phosphoinositide 3-kinase γ attenuates inflammation, obesity, and cardiovascular risk factors. Ann. N.Y. Acad. Sci. 1280, 44-47. doi: 10.1111/nyas.12037.
180. Xu, X., Su, S., Wang, X., Barnes, V., De Miguel, C., and Ownby, D. (2015). Obesity is associated with more activated neutrophils in African American male youth. Int. J. Obes. (Lond). 39, 26-32. doi: 10.1038/ijo.2014.194.
181. Yadav, H., Lee, J. H., Lloyd, J., Walter, P., and Rane, S. G. (2013). Beneficial metabolic effects of a probiotic via butyrate-induced GLP-1 hormone secretion. J. Biol. Chem. 288, 25088-25097. doi: 10.1074/jbc. M113.452516.
182. Yoo, S. R., Kim, Y. J., Park, D. Y., Jung, U. J., Jeon, S. M., Ahn, Y. T., et al. (2013). Probiotics L. plantarum and L. curvatus in combination alter hepatic lipid metabolism and suppress diet-induced obesity. Obesity (Silver Spring) 21, 2571-2578. doi: 10.1002/oby.20428.
183. Yoshimura, A., Ohnishi, S., Orito, C., Kawahara, Y., Takasaki, H., Takeda, H., et al. (2015). Association of peripheral total and differential leukocyte counts with obesity-related complications in young adults. Obes. Facts 8, 1-16. doi: 10.1159/000373881.
184. Zambetti, L. P., and Mortellaro, A. (2014). NLRPs, microbiota, and gut homeostasis: unravelling the connection. J. Pathol. 233, 321-330. doi: 10.1002/path.4357.
185. 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. doi: 10.1016/j.cell.2008.07.043.
186. Zhao, R., Tang, D., Yi, S., Li, W., Wu, C., and Lu, Y. (2014). Elevated peripheral frequencies of Th22 cells: a novel potent participant in obesity and type 2 diabetes. PLoS ONE 9:e85770. doi: 10.1371/journal.pone.0085770.
187. + blood monocytes: their role in infection and inflammation. J. Leukoc. Biol. 81, 584-592. doi: 10.1189/jlb.0806510.