Metabolic signals and innate immune activation in obesity and exercise

Exercise Immunology Review

Volumn 21, Issue , 2015, Pages 58-68

  Ringseis, Robert ^a   Eder, Klaus ^a   Mooren, Frank C ^a   Krüger, Karsten ^a  

^a JUSTUS LIEBIG UNIVERSITY   (Germany)

Author keywords

Adipose tissue; Exercise; Fatty acids; Immune system; Inflammation; Obesity

Indexed keywords

CRYOPYRIN; FATTY ACID; FREE FATTY ACID RECEPTOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INFLAMMASOME; MEMBRANE RECEPTOR; NUCLEOTIDE BINDING OLIGOMERIZATION DOMAIN LIKE RECEPTOR; PATTERN RECOGNITION RECEPTOR; TOLL LIKE RECEPTOR; UNCLASSIFIED DRUG; AUTACOID; CARRIER PROTEIN; G PROTEIN COUPLED RECEPTOR; I KAPPA B; NF-KAPPAB INHIBITOR ALPHA;

COMORBIDITY; DISEASE ASSOCIATION; DISEASE CONTROL; ENDOPLASMIC RETICULUM STRESS; EXERCISE; HUMAN; IMMUNE RESPONSE; INNATE IMMUNITY; MOLECULAR DYNAMICS; MOLECULAR RECOGNITION; NONHUMAN; OBESITY; PROTEIN DETERMINATION; PROTEIN FUNCTION; REVIEW; SIGNAL TRANSDUCTION; TREATMENT RESPONSE; UNFOLDED PROTEIN RESPONSE; ADIPOSE TISSUE; ADVERSE EFFECTS; ANIMAL; BLOOD; DIET; IMMUNOLOGY; INFLAMMATION; KINESIOTHERAPY; KNOCKOUT MOUSE; MACROPHAGE; METABOLISM; MOTOR ACTIVITY; PHYSIOLOGY; SEDENTARY LIFESTYLE;

ADIPOSE TISSUE; ANIMALS; CARRIER PROTEINS; DIET; EXERCISE; EXERCISE THERAPY; FATTY ACIDS, NONESTERIFIED; HUMANS; I-KAPPA B PROTEINS; INFLAMMASOMES; INFLAMMATION; INFLAMMATION MEDIATORS; MACROPHAGES; MICE, KNOCKOUT; MOTOR ACTIVITY; NF-KAPPA B; OBESITY; PHYSICAL EXERTION; RECEPTORS, G-PROTEIN-COUPLED; RECEPTORS, PATTERN RECOGNITION; SEDENTARY LIFESTYLE; SIGNAL TRANSDUCTION; UNFOLDED PROTEIN RESPONSE;

EID: 84928704733     PISSN: 10775552     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Review

References (111)

1. Abaraviciene SM, Lundquist I and Salehi A. Rosiglitazone counteracts palmitate-induced beta-cell dysfunction by suppression of MAP kinase, inducible nitric oxide synthase and caspase 3 activities. Cell Mol Life Sci 65:2256-2265, 2008.
2. Ayna G, Krysko DV, Kaczmarek A, Petrovski G, Vandenabeele P and Fésüs L. ATP release from dying autophagic cells and their phagocytosis are crucial for inflammasome activation in macrophages. PLoS One 7:e40069, 2012.
3. Breckenridge DG, Germain M, Mathai JP, Nguyen M and Shore GC. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 22:8608-8618, 2003.
4. Camus G, Poortmans J, Nys M, Deby-Dupont G, Duchateau J, Deby C and Lamy M. Mild endotoxaemia and the inflammatory response induced by a marathon race. Clin Sci (Lond) 92:415-422, 1997.
5. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM and Burcelin R. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57:1470-1481, 2008.
6. Christiansen T1, Paulsen SK, Bruun JM, Pedersen SB and Richelsen B. Exercise training versus diet-induced weight-loss on metabolic risk factors and inflammatory markers in obese subjects: a 12-week randomized intervention study. Am J Physiol Endocrinol Metab 298:E824-831, 2010.
7. Cnop M, Foufelle F and Velloso LA. Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 18:59-68, 2012.
8. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142:711-725, 2012.
9. da Luz G, Frederico MJ, da Silva S, Vitto MF, Cesconetto PA, de Pinho RA, Pauli JR, Silva AS, Cintra DE, Ropelle ER and De Souza CT. Endurance exercise training ameliorates insulin resistance and reticulum stress in adipose and hepatic tissue in obese rats. Eur J Appl Physiol 111:2015-2023, 2011.
10. Davis JE, Braucher DR, Walker-Daniels J and Spurlock ME. 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, 2011.
11. Deldicque L, Cani PD, Delzenne NM, Baar K and Francaux M. Endurance training in mice increases the unfolded protein response induced by a high-fat diet. J Physiol Biochem 69:215-225, 2013.
12. Deldicque L, Hespel P and Francaux M. Endoplasmic reticulum stress in skeletal muscle: origin and metabolic consequences. Exerc Sport Sci Rev 40:43-49, 2012.
13. Diakogiannaki E and Morgan NG. Differential regulation of the ER stress response by long-chain fatty acids in the pancreatic β-cell. Biochem Soc Trans 36(Pt 5):959-962, 2008.
14. 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 and Donath MY. 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, 2010.
15. Esposito K, Pontillo A, Ciotola M, Di Palo C, Grella E, Nicoletti G and Giugliano D. Weight loss reduces interleukin-18 levels in obese women. J Clin Endocrinol Metab 87:3864-3866, 2002.
16. Fessler MB, Rudel LL and Brown JM. Toll-like receptor signaling links dietary fatty acids to the metabolic syndrome. Curr Opin Lipidol 20:379-385, 2009.
17. Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S and Mathis D. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 15:930-939, 2009.
18. Gombault A, Baron L and Couillin I. ATP release and purinergic signaling in NLRP3 inflammasome activation. Front Immunol 3:414, 2013.
19. Gregor MF, Yang L, Fabbrini E, Mohammed BS, Eagon JC, Hotamisligil GS and Klein S. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 58:693-700, 2009.
20. He Y, Franchi L and Nunez G. TLR agonists stimulate Nlrp3-dependent IL-1β production independently of the purinergic P2X7 receptor in dendritic cells and in vivo. J Immunol 190:334-339, 2013.
21. Himes RW and Smith CW. Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J 24:731-739, 2010.
22. Horng T. Calcium signaling and mitochondrial destabilization in the triggering of the NLRP3 inflammasome. Trends Immunol 35:253-261, 2014.
23. Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA and Latz E. Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9:847-856, 2008.
24. Hotamisligil GS, Arner P, Caro JF, Atkinson RL and Spiegelman BM. Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance. J Clin Invest 95:2409-2415, 1995.
25. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF and Spiegelman BM. IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-α- and obesity-induced insulin resistance. Science 271:665-668, 1996.
26. Hotamisligil GS, Shargill NS and Spiegelman BM. Adipose expression of tumor necrosis factor-α: direct role in obesitylinked insulin resistance. Science 259:87-91, 1993.
27. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell 140:900-917, 2010.
28. Hotamisligil GS. Inflammation and metabolic disorders. Nature 444:860-867, 2006.
29. Ito A, Suganami T, Yamauchi A, Degawa-Yamauchi M, Tanaka M, Kouyama R, Kobayashi Y, Nitta N, Yasuda K, Hirata Y, Kuziel WA, Takeya M, Kanegasaki S, Kamei Y and Ogawa Y. Role of CC chemokine receptor 2 in bone marrow cells in the recruitment of macrophages into obese adipose tissue. J Biol Chem 283:35715-35723, 2008.
30. Jager J, Gremeaux T, Cormont M, Le Marchand-Brustel Y and Tanti JF. Interleukin-1beta-induced insulin resistance in adipocytes through down-regulation of insulin receptor substrate-1 expression. Endocrinology 148:241-251, 2007.
31. Jiao P, Ma J, Feng B, Zhang H, Diehl JA, Chin YE, Yan W and Xu H. FFA-induced adipocyte inflammation and insulin resistance: involvement of ER stress and IKKβ pathways. Obesity (Silver Spring) 19:483-491, 2011.
32. Kadoglou NP, Iliadis F, Liapis CD, Perrea D, Angelopoulou N and Alevizos M. Beneficial effects of combined treatment with rosiglitazone and exercise on cardiovascular risk factors in patients with type 2 diabetes. Diabetes Care 30:2242-2244, 2007.
33. Kadoglou NP, Perrea D, Iliadis F, Angelopoulou N, Liapis C and Alevizos M. Exercise reduces resistin and inflammatory cytokines in patients with type 2 diabetes. Diabetes Care 30:719-721, 2007.
34. Kanneganti TD, Lamkanfi M and Nunez G. Intracellular NOD-like receptors in host defense and disease. Immunity 27:549-559, 2007.
35. Karpe F, Dickmann JR and Frayn KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 60:2441-2449, 2011.
36. Kawanishi N, Mizokami T, Yano H and Suzuki K. Exercise attenuates M1 macrophages and CD8+ T cells in the adipose tissue of obese mice. Med Sci Sports Exerc 45:1684-1693, 2013.
37. Kawanishi N, Yano H, Yokogawa Y and Suzuki K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-dietinduced obese mice. Exerc Immunol Rev 16:105-118, 2010.
38. Kawasaki N, Asada R, Saito A, Kanemoto S and Imaizumi K. Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep 2:799, 2012.
39. Khandekar MJ, Cohen P and Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer 11:886-895, 2011.
40. Kharroubi I, Ladriere L, Cardozo AK, Dogusan Z, Cnop M and Eizirik DL. Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-κB and endoplasmic reticulum stress. Endocrinology 145:5087-5096, 2004.
41. Kim DY, Jung SY and Seo BD. Effect of exercise intervention on changes in free Fatty Acid levels and metabolic risk factors in stroke patients. J Phys Ther Sci 26:275-279, 2014.
42. Kim HJ, Jamart C, Deldicque L, An GL, Lee YH, Kim CK, Raymackers JM and Francaux M. Endoplasmic reticulum stress markers and ubiquitin-proteasome pathway activity in response to a 200-km run. Med Sci Sports Exerc 43:18-25, 2011.
43. Kim K, Kim YH, Lee SH, Jeon MJ, Park SY and Doh KO. Effect of exercise intensity on unfolded protein response in skeletal muscle of rat. Korean J Physiol Pharmacol 18:211-216, 2014.
44. Kim S, Joe Y, Jeong SO, Zheng M, Back SH, Park SW, Ryter SW and Chung HT. Endoplasmic reticulum stress is sufficient for the induction of IL-1β production via activation of the NF-κB and inflammasome pathways. Innate Immun 20:799-815, 2014.
45. Klop B, Elte JW and Cabezas MC. Dyslipidemia in obesity: mechanisms and potential targets. Nutrients 5:1218-1240, 2013.
46. Kruger K, Lechtermann A, Fobker M, Volker K and Mooren FC. Exercise-induced redistribution of T lymphocytes is regulated by adrenergic mechanisms. Brain Behav Immun 22:324-338, 2008.
47. Lagathu C, Yvan-Charvet L, Bastard JP, Maachi M, Quignard-Boulange A, Capeau J and Caron M. Long-term treatment with interleukin-1β induces insulin resistance in murine and human adipocytes. Diabetologia 49:2162-2173, 2006.
48. Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R, Sacks DB, Germain RN, Kastner DL and Chae JJ. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492:123-127, 2012.
49. Leick L, Lindegaard B, Stensvold D, Plomgaard P, Saltin B and Pilegaard H. Adipose tissue interleukin-18 mRNA and plasma interleukin-18: effect of obesity and exercise. Obesity (Silver Spring) 15:356-363, 2007.
50. L'homme L, Esser N, Riva L, Scheen A, Paquot N, Piette J and Legrand-Poels S. Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages. J Lipid Res 54:2998-3008, 2013.
51. 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 and Shi GP. Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15:940-945, 2009.
52. Lukens JR, Dixit VD and Kanneganti TD. Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. Discov Med 12:65-74, 2011.
53. Lumeng CN1, Bodzin JL and Saltiel AR. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Invest 117:175-184, 2007.
54. Lundgren M, Svensson M, Lindmark S, Renstrom F, Ruge T and Eriksson JW. Fat cell enlargement is an independent marker of insulin resistance and 'hyperleptinaemia'. Diabetologia 50:625-633, 2007.
55. Mariathasan S, Weiss DS, Newton K, McBride J, O'Rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM and Dixit VM. Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228-232, 2006.
56. Martinon F, Burns K and Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417-426, 2002.
57. McArdle A, Pattwell D, Vasilaki A, Griffiths RD and Jackson MJ. Contractile activity-induced oxidative stress: cellular origin and adaptive responses. Am J Physiol Cell Physiol 280:C621-627, 2001.
58. McNeela EA, Burke A, Neill DR, Baxter C, Fernandes VE, Ferreira D, Smeaton S, El-Rachkidy R, McLoughlin RM, Mori A, Moran B, Fitzgerald KA, Tschopp J, Petrilli V, Andrew PW, Kadioglu A and Lavelle EC. Pneumolysin activates the NLRP3 inflammasome and promotes proinflammatory cytokines independently of TLR4. PLoS Pathog 6:e1001191, 2010.
59. Medeiros C, Frederico MJ, da Luz G, Pauli JR, Silva AS, Pinho RA, Velloso LA, Ropelle ER and De Souza CT. Exercise training reduces insulin resistance and upregulates the mTOR/p70S6k pathway in cardiac muscle of diet-induced obesity rats. J Cell Physiol 226:666-674, 2011.
60. Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T and Akira S. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol 14:454-460, 2013.
61. Munoz-Planillo R, Kuffa P, Martinez-Colon G, Smith BL, Rajendiran TM and Nunez G. K□efflux is the common trigger of NLRP3 inflammasome activation by bacterial toxins and particulate matter. Immunity 38:1142-1153, 2013.
62. Murakami T, Ockinger J, Yu J, Byles V, McColl A, Hofer AM and Horng T. Critical role for calcium mobilization in activation of the NLRP3 inflammasome. Proc Natl Acad Sci U S A. 109:11282-11287, 2012.
63. Murphy RA, Reinders I, Garcia ME, Eiriksdottir G, Launer LJ, Benediktsson R, Gudnason V, Jonsson PV and Harris TB; Age, Gene/Environment Susceptibility-Reykjavik Study (AGES-Reykjavik). Adipose tissue, muscle, and function: potential mediators of associations between body weight and mortality in older adults with type 2 diabetes. Diabetes Care 37:3213-3219, 2014.
64. Nakamoto N and Kanai T. Role of toll-like receptors in immune activation and tolerance in the liver. Front Immunol 5:221, 2014.
65. Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG and Olefsky JM. 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 282:35279-35292, 2007.
66. Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, Otsu M, Hara K, Ueki K, Sugiura S, Yoshimura K, Kadowaki T and Nagai R. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat Med 15:914-920, 2009.
67. Nov. O, Shapiro H, Ovadia H, Tarnovscki T, Dvir I, Shemesh E, Kovsan J, Shelef I, Carmi Y, Voronov E, Apte RN, Lewis E, Haim Y, Konrad D, Bashan N and Rudich A. Interleukin-1β regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability. PLoS One 8:e53626, 2013.
68. Ogborn DI, McKay BR, Crane JD, Parise G and Tarnopolsky MA. The unfolded protein response is triggered following a single, unaccustomed resistance-exercise bout. Am J Physiol Regul Integr Comp Physiol 307:R664-669, 2014.
69. Ohmura K, Ishimori N, Ohmura Y, Tokuhara S, Nozawa A, Horii S, Andoh Y, Fujii S, Iwabuchi K, Onoe K and Tsutsui H. Natural killer T cells are involved in adipose tissues inflammation and glucose intolerance in diet-induced obese mice. Arterioscler Thromb Vasc Biol 30:193-199, 2010.
70. Oliveira AG, Carvalho BM, Tobar N, Ropelle ER, Pauli JR, Bagarolli RA, Guadagnini D, Carvalheira JB and Saad MJ. Physical exercise reduces circulating lipopolysaccharide and TLR4 activation and improves insulin signaling in tissues of DIO rats. Diabetes 60:784-796, 2011.
71. Oliveira M and Gleeson M. The influence of prolonged cycling on monocyte Toll-like receptor 2 and 4 expression in healthy men. Eur J Appl Physiol 109:251-257, 2010.
72. Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH and Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306:457-461, 2004.
73. Park YM, Myers M and Vieira-Potter VJ. Adipose tissue inflammation and metabolic dysfunction: role of exercise. Mo Med 111:65-72, 2014.
74. Pierre N, Deldicque L, Barbe C, Naslain D, Cani PD and Francaux M. Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet. PLoS One 8:e65061, 2013.
75. Quan J, Liu J, Gao X, Liu J, Yang H, Chen W, Li W, Li Y, Yang W and Wang B. Palmitate induces interleukin-8 expression in human aortic vascular smooth muscle cells via Toll-like receptor 4/nuclear factor-κB pathway (TLR4/NF-κB-8). J Diabetes 6:33-41, 2014.
76. Rask-Madsen C and Kahn CR. Tissue-specific insulin signaling, metabolic syndrome, and cardiovascular disease. Arterioscler Thromb Vasc Biol 32:2052-2059, 2012.
77. Ropelle ER, Pauli JR, Prada PO, de Souza CT, Picardi PK, Faria MC, Cintra DE, Fernandes MF, Flores MB, Velloso LA, Saad MJ and Carvalheira JB. Reversal of diet-induced insulin resistance with a single bout of exercise in the rat: the role of PTP1B and IRS-1 serine phosphorylation. J Physiol 577(Pt 3):997-1007, 2006.
78. Rosa JC, Lira FS, Eguchi R, Pimentel GD, Venancio DP, Cunha CA, Oyama LM, De Mello MT, Seelaender M and do Nascimento CM. Exhaustive exercise increases inflammatory response via Toll like receptor-4 and NF-κBp65 pathway in rat adipose tissue. J Cell Physiol 226:1604-1607, 2011.
79. Rossol M, Pierer M, Raulien N, Quandt D, Meusch U, Rothe K, Schubert K, Schoneberg T, Schaefer M, Krugel U, Smajilovic S, Brauner-Osborne H, Baerwald C and Wagner U. Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors. Nat Commun 3:1329, 2012.
80. Rutkowski DT and Kaufman RJ. A trip to the ER: coping with stress. Trends Cell Biol 14:20-28, 2004.
81. Saxena M and Yeretssian G. NOD-Like Receptors: Master Regulators of Inflammation and Cancer. Front Immunol 5:327, 2014.
82. Schernthaner GH, Kopp HP, Kriwanek S, Krzyzanowska K, Satler M, Koppensteiner R, Schernthaner G. Effect of massive weight loss induced by bariatric surgery on serum levels of interleukin-18 and monocyte-chemoattractant-protein-1 in morbid obesity. Obes Surg 16:709-715, 2006.
83. Schnell S, Schaefer M and Schofl C. Free fatty acids increase cytosolic free calcium and stimulate insulin secretion from beta-cells through activation of GPR40. Mol Cell Endocrinol 263:173-180, 2007.
84. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H and Flier JS. TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116:3015-3025, 2006.
85. Skurk T, Kolb H, Muller-Scholze S, Rohrig K, Hauner H and Herder C. Theproatherogenic cytokine interleukin-18 is secreted by human adipocytes. Eur J Endocrinol 152:863-868, 2005.
86. Snodgrass RG1, Huang S, Choi IW, Rutledge JC and Hwang DH. Inflammasome-mediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids. J Immunol 191:4337-4347, 2013.
87. Spalding KL, Arner E, Westermark PO, Bernard S, Buchholz BA, Bergmann O, Blomqvist L, Hoffstedt J, Naslund E, Britton T, Concha H, Hassan M, Ryden M, Frisen J and Arner P. Dynamics of fat cell turnover in humans. Nature 453:783-787, 2008.
88. Sriwijitkamol A, Christ-Roberts C, Berria R, Eagan P, Pratipanawatr T, De Fronzo RA, Mandarino LJ and Musi N. Reduced skeletal muscle inhibitor of kappaB beta content is associated with insulin resistance in subjects with type 2 diabetes: reversal by exercise training. Diabetes 55:760-767, 2006.
89. Steneberg P, Rubins N, Bartoov-Shifman R, Walker MD and Edlund H. The FFA receptor GPR40 links hyperinsulinemia, hepatic steatosis, and impaired glucose homeostasis in mouse. Cell Metab 1:245-258, 2005.
90. Stensvold D, Slordahl SA and Wisloff U. Effect of exercise training on inflammation status among people with metabolic syndrome. Metab Syndr Relat Disord 10:267-272, 2012.
91. Stern JS, Batchelor BR, Hollander N, Cohn CK and Hirsch J. Adipose-cell size and immunoreactive insulin levels in obese and normal-weight adults. Lancet 2:948-951, 1972.
92. Stienstra R, Joosten LA, Koenen T, van Tits B, van Diepen JA, van den Berg SA, Rensen PC, Voshol PJ, Fantuzzi G, Hijmans A, Kersten S, Muller M, van den Berg WB, van Rooijen N, Wabitsch M, Kullberg BJ, van der Meer JW, Kanneganti T, Tack CJ and Netea MG. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 12:593-605, 2010.
93. Tantiwong P, Shanmugasundaram K, Monroy A, Ghosh S, Li M, De Fronzo RA, Cersosimo E, Sriwijitkamol A, Mohan S and Musi N. NF-κB activity in muscle from obese and type 2 diabetic subjects under basal and exercise-stimulated conditions. Am J Physiol Endocrinol Metab 299:E794-801, 2010.
94. Thyfault JP, Cree MG, Zheng D, Zwetsloot JJ, Tapscott EB, Koves TR, Ilkayeva O, Wolfe RR, Muoio DM and Dohm GL. Contraction of insulin-resistant muscle normalizes insulin action in association with increased mitochondrial activity and fatty acid catabolism. Am J Physiol Cell Physiol 292:C729-739, 2007.
95. Troseid M, Lappegard KT, Mollnes TE, Arnesen H and Seljeflot I. The effect of exercise on serum levels of interleukin-18 and components of the metabolic syndrome. Metab Syndr Relat Disord 7:579-584, 2009.
96. Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, Araujo EP, Vassallo J, Curi R, Velloso LA and Saad MJ. Loss-of-function mutation in Toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56:1986-1998, 2007.
97. Uysal KT, Wiesbrock SM, Marino MW and Hotamisligil GS. Protection from obesity-induced insulin resistance in mice lacking TNF-α function. Nature 389:610-614, 1997.
98. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM and Dixit VD. The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17:179-188, 2011.
99. Wei Y, Wang D, Topczewski F and Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 291:E275-281, 2006.
100. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL and Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112:1796-1808, 2003.
101. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ and Ting JP. Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12:408-415, 2011.
102. Wen H, Miao EA and Ting JP. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39:432-441, 2013.
103. Weyer C, Foley JE, Bogardus C, Tataranni PA and Pratley RE. Enlarged subcutaneous abdominal adipocyte size, but not obesity itself, predicts type II diabetes independent of insulin resistance. Diabetologia 43:1498-1506, 2000.
104. WHO: Preventing Chronic Diseases: a Vital Investment: Geneva, World Health Organization, 2005.
105. 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 and Dosch HM. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 15:921-929, 2009.
106. Wu J and Kaufman RJ. From acute ER stress to physiological roles of the Unfolded Protein Response. Cell Death Differ 13:374-384, 2006.
107. Wu J, Ruas JL, Estall JL, Rasbach KA, Choi JH, Ye L, Bostrom P, Tyra HM, Crawford RW, Campbell KP, Rutkowski DT, Kaufman RJ and Spiegelman BM. The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex. Cell Metab 13:160-169, 2011.
108. Wu J, Sun P, Zhang X, Liu H, Jiang H, Zhu W and Wang H. Inhibition of GPR40 protects MIN6 β cells from palmitateinduced ER stress and apoptosis. J Cell Biochem 113:1152-1158, 2012.
109. Zbinden-Foncea H, Raymackers JM, Deldicque L, Renard P and Francaux M. TLR2 and TLR4 activate p38 MAPK and JNK during endurance exercise in skeletal muscle. Med Sci Sports Exerc 44:1463-1472, 2012.
110. Zbinden-Foncea H, van Loon LJ, Raymackers JM, Francaux M and Deldicque L. Contribution of nonesterified fatty acids to mitogen-activated protein kinase activation in human skeletal muscle during endurance exercise. Int J Sport Nutr Exerc Metab 23:201-209, 2013.
111. Zhong Z, Zhai Y, Liang S, Mori Y, Han R, Sutterwala FS, Qiao L. TRPM2 links oxidative stress to NLRP3 inflammasome activation. Nat Commun 4:1611, 2013.